Saturated hydroxyalkylquinoline acids as leukotriene antagonists

ABSTRACT

Compounds having the formula I: ##STR1## are leukotriene antagonists and inhibitors of leukotriene biosynthesis. These compounds are useful as anti-asthmatic, anti-allergic, anti-inflammatory, and cytoprotective agents. They are also useful in treating angina, cerebral spasm, glomerular nephritis, hepatitis, endotoxemia, uveitis, and allograft rejection.

CROSS-REFERENCE

This is a CIP of U.S. Ser. No. 596,844, Oct. 12, 1990, abandoned.

BACKGROUND OF THE INVENTION

The leukotrienes constitute a group of locally acting hormones, producedin living systems from arachidonic acid. The major leukotrienes areLeukotriene B₄ (LTB₄), LTC₄, LTD₄ and LTE₄. The biosynthesis of theseleukotrienes begins with the action of the enzyme 5-lipoxygenase onarachidonic acid to produce the epoxide known as Leukotriene A₄ (LTA₄),which is converted to the other leukotrienes by subsequent enzymaticsteps. Further details of the biosynthesis as well as the metabolism ofthe leukotrienes are to be found in Leukotrienes and Lipoxygenases, ed.J. Rokach, Elsevier, Amsterdam (1989). The actions of the leukotrienesin living systems and their contribution to various diseases states arealso discussed in the book by Rokach.

The art describes certain quinoline-containing compounds as havingactivity as antagonists of the actions of the leukotrienes. Thus, EP318,093 (Merck) describes compounds of structure A. Structure B isdisclosed in EP 315,399 (Rorer). Structure C is described in EP 348,155(Rorer). ##STR2##

SUMMARY OF THE INVENTION

The present invention relates to saturated hydroxyalkyl quinoline acidshaving activity as leukotriene antagonists, to methods for theirpreparation, and to methods and pharmaceutical formulations for usingthese compounds in mammals (especially humans).

Because of their activity as leukotriene antagonists, the compounds ofthe present invention are useful as anti-asthmatic, anti-allergic,anti-inflammatory, and cytoprotective agents. They are useful intreating angina, cerebral spasm, glomerular nephritis, hepatitis,endotoxemia, uveitis, and allograft rejection.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are best realized by Formula I: ##STR3##herein: R¹ is H, halogen, --CF₃, --CN, --N)₂, or N₃ ;

R² is lower alkyl, lower alkenyl, lower alkynyl, --F₃, --CH₂ F, --CHF₂,CH₂ CF₃, substituted or unsubstituted phenyl, substituted orunsubstituted benzyl, substituted or unsubstituted 2-phenethyl, or twoR² groups joined to the same carbon may form a ring of up to 8 memberscontaining 0-2 heteroatoms chosen from O, S, and N;

R³ is H or R² ;

CR³ R²² may be the radical of a standard amino acid;

R⁴ is halogen, --NO₂, --CN, --OR³ --SR³, NR³ R³, NR³ C(O)R⁷ or R³ ;

R⁵ is H halogen --NO₂ --N₃ --CN, --SR², --NR³ R³, --OR³, lower alkyl, or--C(O)R³ ;

R⁶ is --(CH₂)_(s) --C(R⁷ R⁷)--(CH₂)--R⁸ or --CH₂ C(O)NR¹² R¹² ;

R⁷ is H or C₁ -C₄ alkyl;

R⁸ is A) a monocyclic or bicyclic heterocyclic radical containing from 3to 12 nuclear carbon atoms and 1 or 2 nuclear heteroatoms selected fromN, S or O and with each ring in the heterocyclic radical being formed of5 or 6 atoms, or

B) the radical W-R⁹ ;

R⁹ contains up to 20 carbon atoms and is (1) an alkyl group or (2) analkylcarbonyl group of an organic acyclic or monocyclic carboxylic acidcontaining not more than 1 heteroatom in the ring;

R¹⁰ is --SR¹¹, --OR¹² or --NR¹² R¹² ;

R¹¹ is lower alkyl, --C(O)R¹⁴, unsubstituted phenyl, or unsubstitutedbenzyl;

R¹² is H, R¹¹ or two R¹² groups joined to the same N may form a ring of5 or 6 members containing 1-2 heteroatoms chosen from O, S, and N;

R¹³ is lower alkyl, lower alkenyl, lower alkynyl, --CF₃, or substitutedor unsubstituted phenyl, benzyl, or 2-phenethyl;

R¹⁴ is H or R¹³ ;

R¹⁵ is R³ or halogen;

R¹⁶ is H, C₁ -C₄ alkyl, or OH;

R¹⁷ is lower alkyl, lower alkenyl, lower alkynyl, or substituted orunsubstituted phenyl, benzyl, or 2-phenethyl;

R¹⁸ is lower alkyl, lower alkenyl, lower alkynyl, --CF₃, or substitutedor unsubstituted phenyl, benzyl, or 2-phenethyl;

R¹⁹ is lower alkyl, lower alkenyl, lower alkynyl, --CF₃, or substitutedor unsubstituted phenyl, benzyl, or 2-phenethyl;

R²⁰ is H, C₁ -C₄ alkyl, substituted or unsubstituted phenyl, benzyl,phenethyl, or pyridinyl or two R²⁰ groups joined to the same N may forma saturated ring of 5 or 6 members containing 1-2 heteroatoms chosenfrom O, S, and N;

R²¹ is H or R17;

R²² is R⁴, CHR⁷ OR³, or CHR⁷ SR² ;

m and m' are independently 0-8;

n and n' are independently 0 or 1,

p and p' are independently 0-8;

m+n+p is 1-10 when r is 1 and X² is O, S, S(O), or S(O)₂ ;

m+n+p is 0-10 when r is 1 and X² is CR³ R¹⁶ ;

m+n+p is 0-10 when r is 0;

m'+n'+p' is 0-10;

r and r' are independently 0 or 1;

s is 0-3;

Q¹ is --C(O)OR³, 1H(or 2H)-tetrazol-5-yl, --C(O)OR⁶, --C(O)NHS(O)₂ R¹³,--CN, --C(O)NR¹² R¹², --NR²¹ S(O)₂ R¹³, --NR¹² C(O)NR12R¹², --NR²¹C(O)R¹⁸, --OC(O)NR¹² R¹², --C(O)R¹⁹, --S(O)R¹⁸, --S(O)₂ R¹⁸, --S(O)₂NR¹² R¹², --NO₂, --NR²¹ C(O)OR¹⁷, --C(NR¹² R¹²)=NR¹², --C(R¹³)=NOH; orif Q¹ is --C(O)OH and R²² is --OH, --SH, --CHR⁷ OH or --NHR³, then Q¹and R²² and the carbons through which they are attached may form aheterocyclic ring by loss of water;

Q² is OH or NR²⁰ R²⁰ ;

W is O, S, or NR³ ;

X² and X³ are independently O, S, S(O), S(O)₂, or CR³ R¹⁶ ;

Y is ##STR4## Z¹ and Z² are independently --HET(-R3-R5)--; HET is thediradical of a benzene, a pyridine, a furan, or a thiophene; and thepharmaceutically acceptable salts thereof.

Definitions

The following abbreviations have the indicated meanings:

Et=ethyl

Me=methyl

Bz=benzyl

Ph=phenyl

t-Bu=tert-butyl

i-Pt=isopropyl

n-Pt=normal propyl

c-Hex=cyclohexyl

c-Pt=cyclopropyl

1,1-c-Bu=1,1-bis-cyclobutyl

1,1-c-Pt=1,1-bis-cyclopropyl (e.g., HOCH₂ (1,1-c-Pr)CH₂ CO₂ Me is methyl1-(hydroxymethoxy)cyclopropaneacetate)

c-=cyclo

Ac=acetyl

Tz=1H(or 2H)-tetrazol-5-yl

Th=2--or 3-thienyl

C₃ H₅ =allyl

CHCH₂ CH=1,2-cyclopropanediyl

c-Pen=cyclopentyl

c-Bu=cyclobutyl

phe=benzenediyl

pye=pyridinediyl

fur=furandiyl

thio=thiophenediyl

DEAD=diethyl azodicarboxylate

DHP=dihydropyran

DIAD=diisopropyl azodicarboxylate

r.t.=room temperature

Alkyl, alkenyl, and alkynyl are intended to include linear, branched,and cyclic structures and combinations thereof.

"Alkyl" includes "lower alkyl" and extends to cover carbon fragmentshaving up to 20 carbon atoms. Examples of alkyl groups include octyl,nonyl, norbornyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl,eicosyl, 3,7-diethyl-2,2-dimethyl-4-propylnonyl, 2-(cyclododecyl)ethyl,adamantyl, and the like.

"Lower alkyl" means alkyl groups of from 1 to 7 carbon atoms. Examplesof lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl,sec-and tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, 2-methylcyclopropyl,cyclopropylmethyl, and the like.

"Lower alkenyl" means alkenyl groups of 2 to 7 carbon atoms. Examples oflower alkenyl groups include vinyl, allyl, isopropenyl, pentenyl,hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, 1-propenyl, 2-butenyl, 2- methyl-2-butenyl, and the like.

"Lower alkynyl" means alkynyl groups of 2 to 7 carbon atoms. Examples oflower alkynyl groups include ethynyl, propargyl, 3-methyl-l-pentynyl,2-heptynyl, and the like.

"Alkylcarbonyl" means alkylcarbonyl groups of 1 to 21 carbon atoms of astraight, branched or cyclic configuration. Examples of alkylcarbonylgroups are 2-methylbutanoyl, octadecanoyl, 11-cyclohexylundecanoyl andthe like. Thus, the 11-cyclohexylundecanoyl group is c-Hex-(CH₂)₁₀--C(O)--.

Substituted phenyl, benzyl, 2-phenethyl and pyridinyl means structureswith 1 or 2 substituents on the aromatic ring selected from lower alkyl,R¹⁰, NO₂, SCF₃, halogen, --C(O)R⁷, --C(O)R¹⁰, CN, CF₃, and CN₄ H.

Halogen means F, C1, Br and I.

The prodrug esters of Q1 (i.e., when Q¹ =--C(O)OR⁶) are intended to meanthe esters such as are described by Saari et al., J. Med. Chem., 21, No.8, 746-753 (1978), Sakamoto et al., Chem. Pharm. Bull., 32, No. 6,2241-2248 (1984) and Bundgaard et al., J. Med. Chem., 30, No. 3,451-454(1987). Within the definition of R⁸ some representative monocyclic orbicyclic heterocyclic radicals are:

2,5-dioxo-l-pyrrolidinyl,

(3-pyridinylcarbonyl)amino,

1,3-dihydro-l,3-dioxo-2H-isoindol-2-yl,

1,3-dihydro-2H-isoindol-2-yl,

2,4-imidazolinedion-l-yl,

2,6-piperidinedion-l-yl,

2-imidazolyl,

2-oxo-l,3-dioxolen-4-yl,

piperidin-1-yl,

morpholin-1-yl, and

piperazin-1-yl.

When Q¹ and R²² and the carbons through which they are attached form aring, the rings thus formed include lactones, lactams, and thiolactones.

It is intended that the definitions of any substituent (e.g., R¹ R² m, Xetc.) in a particular molecule be independent of its definitionselsewhee in the molecule. Thus, --NR³ R³ represents --NHH, --NHCH₃,--NHC₆ H₅, etc.

The heterocycles formed when two R³, R¹², or R²⁰ groups join through Ninclude pyrrolidine, piperidine, morpholine, thiamorpholine, piperazine,and N-methylpiperazine.

"Standard amino acids", the radical of which may be CR³ R²², means thefollowing amino acids: alanine, asparagine, aspattic acid, arginine,cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine,leucine, lysine, methionine, phenylalanine, proline, serine, threonine,tryptophan, tyrosine, and valine. (See F.H.C. Crick, Symposium of theSociety of Experimental Biology, 12, 140 (1958)).

Some of the compounds described herein contain one or more centers ofasymmetry and may thus give rise to diastereoisomers and opticalisomers. The present invention is meant to comprehend such possiblediastereoisomers as well as their racemic and resolved, optically activeforms. Optically active (R) and (S) isomers may be resolved usingconventional techniques.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Preferred compounds of Formula I are those wherein:

R¹ is H, halogen, CF₃, or --CN;

R² is C₁ -C₄ alkyl, --CF₃, --CHF₂, --CH₂ F, or two R² groups joined tothe same carbon may form a ring of up to 6 carbons;

R³ is H or R² ;

CR³ R²² may be the radical of a standard amino acid;

R⁴ is --OR³, --SR³, NR³ R³, NHC(O)CH₃, or R³ ;

R⁵ is H or halogen;

R⁶ is --(CH₂)s--C(R⁷ R⁷)--(CH₂)_(s) --R⁸ or --CH₂ C(O)NR¹² R¹² ;

R⁷ is H or C₁ -C₄ alkyl;

R⁸ is A) a monocyclic or bicyclic heterocyclic radical containing from 3to 12 nuclear carbon atoms and 1 or 2 nuclear heteroatoms selected fromN, S or O and with each ring in the heterocyclic radical being formed of5 or 6 atoms, or

B) the radical W-R⁹ ;

R⁹ contains up to 20 carbon atoms and is (1) an alkyl group or (2) analkylcarbonyl group;

R¹⁰ is --SR¹¹, --OR¹² or --NR¹² R¹² ;

R¹¹ is lower alkyl, --C(O)R¹⁴, unsubstituted phenyl, or unsubstitutedbenzyl;

R¹² is H, R¹¹ or two R¹² groups joined to the same N may form a ring of5 or 6 members containing 1-2 heteroatoms chosen from O, S, and N;

R¹³ i s lower alkyl, --CF₃, or substituted or unsubstituted phenyl,benzyl, or 2-phenethyl;

R¹⁴ is H or R¹³ ;

R¹⁵ is R³ or halogen;

R¹⁶ is H, C₁ -C₄ alkyl, or OH;

R²² is R⁴, --CH₂ OR³, or --CH₂ SR² ;

m and m' are independently 0-4;

n and n' are independently 0 or 1;

p and p' are independently 0-4;

m+n+p is 1-9 when r is 1 and X² is O or S;

m+n+p is 0-9 when r is 1 and X² is CR³ R¹⁶ ;

m+n+p is 0-9 when r is 0;

m'+n'+p' is 1-9,

r and r' are independently 0 or 1;

s is 0-3;

Q¹ is --C(O)OR³, 1H(or 2H)-tetrazol-5-yl, -C(O)OR⁶, --C(O)NHS(O)₂ R¹³,--C(O)NR¹² R¹², --NHS(O)₂ R¹³ ; or if Q¹ is C(O)OH and R²² is --OH,--SH, --CH₂ OH or --NHR³ then Q¹ and R²² and the carbons through whichthey are attached may form a heterocyclic ring by loss of water;

Q² is OH;

W is O, S, or NH;

X² and X³ are independently O, S, or CR³ R¹⁶ ;

Y is ##STR5## Z¹ and Z² are independently --HET(--R³ --R⁵)--; HET is thediradical of a benzene, pyridine, furan, or thiophene; and thepharmaceutically acceptable salts thereof.

Another group of preferred compounds are those wherein the R²² α to Q¹is lower alkyl, CF₃, or substituted or unsubstituted phenyl.

More preferred compounds of Formula I are represented by Formula Ia:##STR6## wherein: R¹ is H, halogen, CN, or CF₃ ;

R²² is R³, --CH₂ OR³, or --CH₂ SR² ;

Q1 is --C(O)OH, 1H(or 2H)-tetrazol-5-yl, --C(O)NHS(O)₂ R¹³, --C(O)NR¹²R¹², or --NHS(O)₂ R¹³ ;

m' is 2 or 3;

p' is 0 or 1;

m+p is 1-5;

the remaining definitions are as in Formula I; and the pharmaceuticallyacceptable salts thereof.

Another group of more preferred compounds are as in Formula Ia, wherein:

m' is 0;

and the remaining definitions are as in Formula Ia.

The most preferred compounds of Formula Ia also have a lower alkyl onthe carbon α to the group Q¹.

Another group of more preferred compounds of Formula I are representedby Formula Ib: ##STR7## wherein: R¹ is H, halogen, CN, or CF₃ ;

R²² is R³, --CH₂ OR³, or --CH₂ SR² ;

Q¹ is --(O)OH, 1H(or 2H)-tetrazolyl, --(O)NHS(O)₂ R¹³, --C(O)NR¹² R¹²,or --NHS(O)₂ R¹³ ;

m is 0, 2, or 3;

p is 0 or 1;

p' is 1-4;

m+p is 0-4;

the remaining definitions are as in Formula I; and the pharmaceuticallyacceptable salts thereof.

Salts

The pharmaceutical compositions of the present invention comprise acompound of Formula I as an active ingredient or a pharmaceuticallyacceptable salt, thereof, and may also contain a pharmaceuticallyacceptable carrier and optionally other therapeutic ingredients. Theterm "pharmaceutically acceptable salts" refers to salts prepared frompharmaceutically acceptable non-toxic bases including inorganic basesand organic bases. Salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc and the like. Particularlypreferred are the ammonium, calcium, magnesium, potassium and sodiumsalts. Salts derived from pharmaceutically acceptable organic non-toxicbases include salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as arginine, betaine,caffeine, choline, N,N'-dibenzylethylene-diamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and thelike. Particularly preferred are citric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric and tartaric acids.

It will be understood that in the discussion of methods of treatmentwhich follows, references to the compounds of Formula I are meant toalso include the pharmaceutically acceptable salts.

Utilities

The compounds of the present invention have modest activity asinhibitors of leukotriene biosynthesis, and are of utility principallybecause of their excellent activity as antagonists of the actions of theleukotrienes.

The ability of the compounds of Formula I to antagonize the actions ofthe leukotrienes makes them useful for preventing or reversing thesymptoms induced by the leukotrienes in a human subject. This antagonismof the actions of leukotrienes indicates that the compounds andpharmaceutical compositions thereof are useful to treat, prevent, orameliorate in mammals and especially in humans: 1) pulmonary disordersincluding diseases such as asthma, chronic bronchitis, and relatedobstructive airway diseases, 2) allergies and allergic reactions such asallergic rhinitis, contact dermatitis, allergic conjunctivitis, and thelike, 3) inflammation such as arthritis or inflammatory bowel disease,4) pain, 5) skin disorders such as psoriasis, atopic eczema, and thelike, 6) cardiovarcular disorders such as angina, myocardial ischemia,hypertension, platelet aggregation and the like, 7) renal insufficiencyarising from ischaemia induced by immunological or chemical(cyclosporin) etiology, 8) migraine or cluster headache, 9) ocularconditions such as uveitis, 10) heptaitis resulting from chemical,immunological or infections stimuli, 11) trauma or shock states such asburn injuries, endotoxemia and the like, 12) allograft rejection 13)prevention of side effects associated with therapeutic administration ofcytokines such as Interleukin II and tumor mecrosis factor, 14) chroniclung diseases such as cystic fibrosis, bronchitis and other small andlarge-airway diseases, and 15) cholecystitis.

Thus, the compounds of the present invention may also be used to treator prevent mammalian (especially, human) disease states such as erosivegartritis; erosive esophagitis; diarrhea; cerebral spasm; prematurelabor; spontaneous abortion; dysmenorrhea; ischemia; noxiousagent-induced damage or necrosis of hepatic, pancreatic, renal, ormyocardial tissue; liver parenchymal damage caused by hepatoxic agentssuch as CCl₄ and D-galactosamine; ischemic renal failure;disease-induced hepatic damage; bile salt induced pancreatic or gastricdamage; trauma- or stress-induced cell damage; and glycerol-inducedrenal failure. The compounds also exhibit cytoprotective action.

The cytoprotective activity of a compound may be observed in bothanimals and man by noting the increased resistance of thegastrointestinal mucosa to the noxious effects of strong irritants, forexample, the ulcerogenic effects of aspirin or indomethacin. In additionto lessening the effect of non-steroidal anti-inflammatory drugs on thegastrointestinal tract, animal studies show that cytoprotectivecompounds will prevent gastric lesions induced by oral administration ofstrong acids, strong bases, ethanol, hypertonic saline solutions and thelike.

Two assays can be used to measure cytoprotective ability. These assaysare; (A) an ethanol-induced lesion assay and (B) an indomethacin-inducedulcer assay and are described in EP 140,684.

Dose Ranges

The magnitude of prophylactic or therapeutic dose of a compound ofFormula I will, of course, vary with the nature of the severity of thecondition to be treated and with the particular compound of Formula Iand its route of administration. It will also vary according to the age,weight and response of the individual patient. In general, the dailydose range for anti-asthmatic, anti-allergic or anti-inflammatory useand generally, uses other than cytoprotection, lie within the range offrom about 0.001 mg to about 100 mg per kg body weight of a mammal,preferably 0.01 mg to about 10 mg per kg, and most preferably 0.1 to 1mg per kg, in single or divided doses. On the other hand, it may benecessary to use dosages outside these limits in some cases.

For use where a composition for intravenous administration is employed,a suitable dosage range for anti-asthmatic, anti-inflammatory oranti-allergic use is from about 0.001 mg to about 25 mg (preferably from0.01 mg to about 1 mg) of a compound of Formula I per kg of body weightper day and for cytoprotective use from about 0.1 mg to about 100 mg(preferably from about 1 mg to about 100 mg and more preferably fromabout 1 mg to about 10 mg) of a compound of Formula I per kg of bodyweight per day.

In the case where an oral composition is employed, a suitable dosagerange for anti-asthmatic, anti-inflammatory or anti-allergic use is,e.g. from about 0.01 mg to about 100 mg of a compound of Formula I perkg of body weight per day, preferably from about 0.1 mg to about 10 mgper kg and for cytoprotective use from 0.1 mg to about 100 mg(preferably from about 1 mg to about 100 mg and more preferably fromabout 10 mg to about 100 mg) of a compound of Formula I per kg of bodyweight per day.

For the treatment of diseases of the eye, ophthalmic preparations forocular administration comprising 0.001-1% by Weight solutions orsuspensions of the compounds of Formula I in an acceptable ophthalmicformulation may be used.

The exact amount of a compound of the Formula I to be used as acytoprotective agent will depend on, inter alia, whether it is beingadministered to heal damaged cells or to avoid future damage, on thenature of the damaged cells (e.g., gastrointestinal ulcerations vs.nephrotic necrosis), and on the nature of the causative agent. Anexample of the use of a compound of the Formula I in avoiding futuredamage would be co-administration of a compound of the Formula I with anon-steroidal anti-inflammatory drug that might otherwise cause suchdamage (for example, indomethacin). For such use, the compound ofFormula I is administered from 30 minutes prior up to 30 minutes afteradministration of the NSAID. Preferably it is administered prior to orsimultaneously with the NSAID, (for example, in a combination dosageform).

Pharmaceutical Compositions

Any suitable route of administration may be employed for providing amammal, especially a human with an effective dosage of a compound of thepresent invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like.

The pharmaceutical compositions of the present invention comprise acompound of Formula I as an active ingredient or a pharmaceuticallyacceptable salt thereof, and may also contain a pharmaceuticallyacceptable carrier and optionally other therapeutic ingredients. Theterm "pharmaceutically acceptable salts" refers to salts prepared frompharmaceutically acceptable non-toxic bases or acids including inorganicbases or acids and organic bases or acids.

The compositions include compositions suitable for oral, rectal,topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (nasal or buccalinhalation), or nasal administration, although the most suitable routein any given case will depend on the nature and severity of theconditions being treated and on the nature of the active ingredient.They may be conveniently presented in unit dosage form and prepared byany of the methods well-known in the art of pharmacy.

For administration by inhalation, the compounds of the present inventionare conveniently delivered in the form of an aerosol spray presentationfrom pressurized packs or nebulisers. The compounds may also bedelivered as powders which may be formulated and the powder compositionmay be inhaled with the aid of an insufflation powder inhaler device.The preferred delivery system for inhalation is a metered doseinhalation (MDI) aerosol, which may be formulated as a suspension orsolution of compound I in suitable propellants, such as fluorocarbons orhydrocarbons.

Suitable topical formulations of Compound I include transdermal devices,aerosols, creams, ointments, lotions, dusting powders, and the like.

In practical use, the compounds of Formula I can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like in the case of oral liquidpreparations, such as, for example, suspensions, elixirs and solutions;or carriers such as starches, sugars, microcrystalline cellulose,diluents, granulating agents, lubricants, binders, disintegrating agentsand the like in the case of oral solid preparations such as, forexample, powders, capsules and tablets, with the solid oral preparationsbeing preferred over the liquid preparations. Because of their ease ofadministration, tablets and capsules represent the most advantageousoral dosage unit form in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be coated by standardaqueous or nonaqueous techniques.

In addition to the common dosage forms set out above, the compounds ofFormula I may also be administered by controlled release means and/ordelivery devices such as those described in U.S. Pat. Nos. 3,845,770;3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719, thedisclosures of which are hereby incorporated herein by reference.

Pharmaceutical compositions of the present invention suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient, as a powder or granules or as a solution or a suspension inan aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or awater-in-oil liquid emulsion. Such compositions may be prepared by anyof the methods of pharmacy but all methods include the step of bringinginto association the active ingredient with the carrier whichconstitutes one or more necessary ingredients. In general, thecompositions are prepared by uniformly and intimately admixing theactive ingredient with liquid carriers or finely divided solid carriersor both, and then, if necessary, shaping the product into the desiredpresentation. For example, a tablet may be prepared by compression ormolding, optionally with one or more accessory ingredients. Compressedtablets may be prepared by compressing in a suitable machine, the activeingredient in a free-flowing form such as powder or granules, optionallymixed with a binder, lubricant, inert diluent, surface active ordispersing agent. Molded tablets may be made by molding in a suitablemachine, a mixture of the powdered compound moistened with an inertliquid diluent. Desirably, each tablet contains from about 2.5 mg toabout 500 mg of the active ingredient and each cachet or capsulecontains from about 2.5 to about 500 mg of the active ingredient.

The following are examples of representative pharmaceutical dosage formsfor the compounds of Formula I:

    ______________________________________                                        Injectable Suspension (I.M.)                                                                           mg/ml                                                ______________________________________                                        Compound of Formula I    10                                                   Methylcellulose          5.0                                                  Tween 80                 0.5                                                  Benzyl alcohol           9.0                                                  Benzalkonium chloride    1.0                                                  Water for injection to a total volume of 1 ml                                 ______________________________________                                        Tablet                   mg/tablet                                            ______________________________________                                        Compound of Formula I    25                                                   Microcrystalline Cellulose                                                                             415                                                  Providone                14.0                                                 Pregelatinized Starch    43.5                                                 Magnesium Stearate       2.5                                                                           500                                                  ______________________________________                                        Capsule                  mg/capsule                                           ______________________________________                                        Compound of Formula I    25                                                   Lactose Powder           573.5                                                Magnesium Stearate       1.5                                                                           600                                                  ______________________________________                                        Aerosol                  Per canister                                         ______________________________________                                        Compound of Formula I    24      mg                                           Lecithin, NF Liquid Concentrate                                                                        1.2     mg                                           Trichlorofluoromethane, NF                                                                             4.025   gm                                           Dichlorodifluoromethane, NF                                                                            12.15   gm                                           ______________________________________                                    

Combinations with other drugs

In addition to the compounds of Formula I, the pharmaceuticalcompositions of the present invention can also contain other activeingredients, such as cyclooxygenase inhibitors, non-steroidalanti-inflammatory drugs (NSAIDs), peripheral analgesic agents such aszomepirac diflunisal and the like. The weight ratio of the compound ofthe Formula I to the second active ingredient may be varied and willdepend upon the effective dose of each ingredient. Generally, aneffective dose of each will be used. Thus, for example, when a compoundof the Formula I is combined with an NSAID the weight ratio of thecompound of the Formula I to the NSAID will generally range from about1000:1 to about 1:1000, preferably about 200:1 to about 1:200.Combinations of a compound of the Formula I and other active ingredientswill generally also be within the aforementioned range, but in eachcase, an effective dose of each active ingredient should be used.

NSAIDs can be characterized into five groups:

(1) the propionic acid derivatives;

(2) the acetic acid derivatives;

(3) the fenamic acid derivatives;

(4) the oxicams; and

(5) the biphenylcarboxylic acid derivatives; or a pharmaceuticallyacceptable salt thereof.

The propionic acid derivatives which may be used comprise: alminoprofen,benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen,flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen,oxaprozin, pirprofen, prano-profen, suprofen, tiaprofenic acid, andtioxaprofen. Structurally related propionic acid derivatives havingsimilar analgesic and anti-inflammatory properties are also intended tobe included in this group.

Thus, "propionic acid derivatives" as defined herein are non-narcoticanalgesics/non-steroidal anti-inflammatory drugs having a free--CH(CH₃)COOH or --CH₂ CH₂ COOH group (which optionally can be in theform of a pharmaceutically acceptable salt group, e.g., --CH(CH₃)COO⁻Na⁺ or --CH₂ CH₂ COO⁻ Na⁺), typically attached directly or via acarbonyl function to a ring system, preferably to an aromatic ringsystem.

The acetic acid derivatives which may be used comprise: indomethacin,which is a preferred NSAID, acemetacin, alclofenac, clidanac,diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin andzomepirac. Structually related acetic acid derivatives having similaranalgesic and anti-inflammatory properties are also intended to beencompassed by this group.

Thus, "acetic acid derivatives" as defined herein are non-narcoticanalgesics/non-steroidal anti-inflammatory drugs having a free --CH₂COOH group (which optionally can be in the form of a pharmaceuticallyacceptable salt group, e.g. --CH₂ COO⁻ Na⁺), typically attached directlyto a ring system, preferably to an aromatic or heteroaromatic ringsystem.

The fenamic acid derivatives which may be used comprise: flufenamicacid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamicacid. Structurally related fenamic acid derivatives having similaranalgesic and anti-inflammatory properties are also intended to beencompassed by this group.

Thus, "fenamic acid derivatives" as defined herein are non-narcoticanalgesics/non-steroidal anti-inflammatory drugs which contain the basicstructure: ##STR8## which can bear a variety of substituents and inwhich the free --COOH group can be in the form of a pharmaceuticallyacceptable salt group, e.g., --COO⁻ Na⁺. The biphenylcarboxylic acidderivatives which can be used comprise:diflunisal and flufenisal.Structurally related biphenylcarboxylic acid derivatives having similaranalgesic and anti-inflammatory properties are also intended to beencompassed by this group.

Thus, "biphenylcarboxylic acid derivatives" as defined herein arenon-narcotic analgesics/non-steroidal anti-inflammatory drugs whichcontain the basic structure: ##STR9## which can bear a variety ofsubstituents and in which the free --COOH group can be in the form of apharmaceutically acceptable salt group, e.g., --COO⁻ Na⁺.

The oxicams which can be used in the present invention comprise:isoxicam, piroxicam, sudoxicam and tenoxican. Structurally relatedoxicams having similar analgesic and anti-inflammatory properties arealso intended to be encompassed by this group.

Thus, "oxicams" as defined herein are non narcoticanalgesics/non-steroidal anti-inflammatory drugs which have the generalformula: ##STR10## wherein R is an aryl or heteroaryl ring system.

The following NSAIDs may also be used: amfenac sodium, aminoprofen,anitrazafen, antrafenine, auranofin, bendazac lysinate, benzydanine,beprozin, broperamole, bufezolac, cinmetacin, ciproquazone, cloximate,dazidamine, deboxamet, delmetacin, detomidine, dexindoprofen, diacerein,di-fisalamine, difenpyramide, emorfazone, enfenamic acid, enolicam,epirizole, etersalate, etodolac, etofenamate, fanetizole mesylate,fenclorac, fendosal, fenflumizole, feprazone, floctafenine, flunixin,flunoxaprofen, fluproquazone, fopirtoline, fosfosal, furcloprofen,glucametacin, guaimesal, ibuproxam, isofezolac, isonixim, isoprofen,isoxicam, lefetamine HCl, leflunomide, lofemizole, lonazolac calcium,lotifazole, loxoprofen, lysin clonixinate, meclofenamate sodium,meseclazone, nabumetone, nictindole, nimesulide, orpanoxin, oxametacin,oxapadol, perisoxal citrate, pimeprofen, pimetacin, piproxen, pirazolac,pirfenidone, proglumetacin maleate, proquazone, pyridoxiprofen,sudoxicam, talmetacin, talniflumate, tenoxicam, thiazolinobutazone,thielavin B, tiaramide HCl, tiflamizole, timegadine, tolpadol, tryptamidand ufenamate.

The following NSAIDs, designated by company code number (see e.g.,Pharmaprojects), may also be used:

480156S, AA861, AD1590, AFP802, AFP860, AI77B, AP504, AU8001, BPPC,BW540C, CHINOIN 127, CN100, EB382, EL508, F1044, GV3658, ITF182,KCNTEI6090, KME4, LA2851, MR714, MR897, MY309, ON03144, PR823, PV102,PV108, R830, RS2131, SCR152, SH440, SIR133, SPAS510, SQ27239, ST281,SY6001, TA60, TAI-901 (4-benzoyl-1-indancarboxylic acid), TVX2706,U60257, UR2301, and WY41770.

Finally, NSAIDs which may also be used include the salicylates,specifically acetyl salicylic acid and the phenylbutazones, andpharmaceutically acceptable salts thereof.

In addition to indomethacin, other preferred NSAIDS are acetyl salicylicacid, diclofenac, fenbufen, fenoprofen, flurbiprofen, ibuprofen,ketoprofen, naproxen, phenylbutazone, piroxicam, sulindac and tolmetin.

Pharmaceutical compositions comprising the Formula I compounds may alsocontain inhibitors of the biosynthesis of the leukotrienes such as aredisclosed in EP 138,481 (Apr. 24,1985), EP 115,394 (Aug. 8, 1984), EP136,893 (Apr. 10, 1985), and EP 140,709 (May 8, 1985), which are herebyincorporated herein by reference.

The compounds of the Formula I may also be used in combination withleukotriene antagonists such as those disclosed in EP 106,565 (Apr. 25,1984) and EP 104,885 (Apr. 4, 1984) which are hereby incorporated hereinby reference and others known in the art such as those disclosed in EPApplication Nos. 56,172 (Jul. 21, 1982) and 61,800 (Jun. 10, 1982); andin U.K. Patent Specification No. 2,058,785 (Apr. 15, 1981), which arehereby incorporated herein by reference.

Pharmaceutical compositions comprising the Formula I compounds may alsocontain as the second active ingredient, prostaglandin antagonists suchas those disclosed in EP 11,067 (May 28, 1980) or thromboxaneantagonists such as those disclosed in U.S. Pat. No. 4,237,160. They mayalso contain histidine decarboxylase inhibitors such asa-fluoromethyl-histidine, described in U.S. Pat. No. 4,325,961. Thecompounds of the Formula I may also be advantageously combined with anH₁ or H₂ --receptor antagonist, such as for instance acetamazole,aminothiadiazoles disclosed in EP 40,696 (Dec. 2, 1981), benadryl,cimetidine, famotidine, framamine, histadyl, phenergan, ranitidine,terrenadine and like compounds, such as those disclosed in U.S. Pat.Nos. 4,283,408; 4,362,736; and 4,394,508. The pharmaceuticalcompositions may also contain a K⁺ /H⁺ ATPase inhibitor such asomeprazole, disclosed in U.S. Pat. No. 4,255,431, and the like.Compounds of Formula I may also be usefully combined with most cellstabilizing agents, such as1,3-bis(2-carboxy-chromon-5-yloxy)-2-hydroxypropane and relatedcompounds described in British Patent Specifications 1,144,905 and1,144,906. Another useful pharmaceutical composition comprises theFormula I compounds in combination with serotonin antagonists such asmethysergide, the serotonin antagonists described in Nature, Vol. 316,pages 126-131, 1985, and the like. Each of the references referred to inthis paragraph is hereby incorporated herein by reference.

Other advantageous pharmaceutical compositions comprise the Formula Icompounds in combination with anti-cholinergics such as ipratropiumbromide, bronchodilators such as the beta agonist salbutamol,metaproterenol, terbutaline, fenoterol and the like, and theanti-asthmatic drugs theophylline, choline theophyllinate andenprofylline, the calcium antagonists nifedipine, diltiazem,nitrendipine, verapamil, nimodipine, felodipine, etc. and thecorticosteroids, hydrocortisone, methylpred-nisolone, betamethasone,dexamethasone, beclomethasone, and the like.

Representative Compounds

Table I illustrates compounds representative of the present invention.Table II provides elemental analyses for compounds of Table I.

                                      TABLE I                                     __________________________________________________________________________     ##STR11##                                                                    EX.                                                                              * R.sup.1                                                                           Y       A              B                                             __________________________________________________________________________    1  RS                                                                              7-Cl                                                                              CHCH.sub.2 CH                                                                         SCH.sub.2 CHMeCO.sub.2 H                                                                     (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        2  RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CHMeCO.sub.2 H                                                                     (CH.sub.2).sub.2 (1,2-phe)(1-c-Bu)OH          3  RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2 CH                                                                  SCH.sub.2 CHEtCO.sub.2 H                                                                     (CH.sub.2).sub.2 (4-Cl-1,2-phe)CMe.sub.2                                      OH                                            4  RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CHMeCO.sub.2 H                                                                     (1,3-phe)C.sub.2 OH                           5  RS                                                                              7-Cl                                                                              CHCH.sub.2 CH                                                                         S(CH.sub.2).sub.2 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (1,2-phe)CO.sub.2 H          6  S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 (S)CHEtCO.sub.2 H                                                                  (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        7  S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 (R)CH(NH.sub.2)CO.sub.2 H                                                          (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        8  S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 (S)CHMeCO.sub. 2 H                                                                 (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        9  S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 (S)CH(n-Pr)CO.sub.2 H                                                              (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        10 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2 CH                                                                  SCH.sub.2 CHEtCO.sub.2 H                                                                     (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        11 RS                                                                              7-Cl                                                                              CHCBr.sub.2 CH                                                                        SCH.sub.2 CHEtCO.sub.2 H                                                                     (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        12 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CMe.sub.2 CO.sub.2 H                                                               (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        13 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CHMeCO.sub.2 H                                                                     (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        14 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.2 CO.sub.2 H                                                                 (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        15 RS                                                                              7-Br                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CHMeCO.sub.2 H                                                                     (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        16 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2)CMe.sub.2 OH                                                                      (CH.sub.2).sub.2 (1,2-phe)CHMeCO.sub.2 H      17 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CHEtCO.sub.2 H                                                                     S(CH.sub.2).sub.2 CMe.sub.2 OH                18 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CHMeCO.sub.2 H                                                                     (CH.sub.2).sub.2 (1,2-phe)C(CF.sub.3).sub.                                    2 OH                                          19 RS                                                                              7-Cl                                                                              CHCH.sub.2 CH                                                                         SCH.sub.2 CHEtCO.sub.2 H                                                                     (CH.sub.2).sub.2 (1,3-phe)CMe.sub.2 OH        20 RS                                                                              7-Cl                                                                              CHCH.sub.2 CH                                                                         SCH.sub.2 CHEtCO.sub.2 H                                                                     SCH.sub.2 CMe.sub.2 CMe.sub.2 OH              21 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.2 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (1,2-phe)CO.sub.2 H          22 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.2 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (1,2-phe)CONH.sub.2          23 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CHMeCO.sub.2 H                                                                     SCH.sub.2 (1,2-phe)CMe.sub.2 OH               24 RS                                                                              7-CF.sub.3                                                                        CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CHMeCO.sub.2 H                                                                     (CH.sub.2).sub.2 (1,4-phe)CMe.sub.2 OH        25 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CH(OMe)CO.sub.2 H                                                                  (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        26 RS                                                                              7-Cl                                                                              CHCH.sub.2 CH                                                                         SCH.sub.2 CHEtCO.sub.2 H                                                                     (CH.sub.2).sub.2 (1,2-phe)CH(CF.sub.3)OH      27 RS                                                                              H   CHCH.sub.2 CH                                                                         SCH.sub.2 CHMeCO.sub.2 H                                                                     (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        28 RS                                                                              H   CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CHEtCO.sub.2 H                                                                     (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        29 RS                                                                              7-Br                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CHEtCO.sub.2 H                                                                     (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        30 RS                                                                              7-CN                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CHEtCO.sub.2 H                                                                     (CH.sub.2).sub.2 (1,2-phe)CMeEtOH             31 RS                                                                              7-Br                                                                              CHCH.sub.2 CH                                                                         SCH.sub.2 CHEtCO.sub.2 H                                                                     (CH.sub.2).sub.2 (1,2-phe)CEt.sub.2 OH        32 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CHMeCO.sub.2 H                                                                     (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2                                           NH.sub.2                                      33 RS                                                                              7-Cl                                                                              CHCH.sub.2 CH                                                                         SCH.sub.2 CHEtCO.sub.2 H                                                                     (CH.sub.2).sub.2 (1,2-phe)CHMeNHMe            34 RS                                                                              7-Br                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CHEtCO.sub.2 H                                                                     (CH.sub.2).sub.2 (1,2-phe)CHMeNMe.sub.2       35 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CHEtCO.sub.2 H                                                                     (CH.sub.2).sub.2 (2,5-fur)CMe.sub.2 OH        36 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CHEtCO.sub.2 H                                                                     (CH.sub.2).sub.2 (2,6-pye)CMe.sub.2 OH        37 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CHEtCO.sub.2 H                                                                     (CH.sub.2).sub.2 (4,2-pye)CMe.sub.2 OH        38 RS                                                                              7-Cl                                                                              CHCH.sub.2 CH                                                                         SCH.sub.2 CHEtCO.sub.2 H                                                                     (2,5-thio)CMe.sub.2 OH                        39 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CHEtCO.sub.2 H                                                                     (3,2-pye)CMe.sub.2 OH                         40 RS                                                                              7-Br                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CHEtCO.sub.2 H                                                                     (1,4-phe)CMe.sub. 2 OH                        41 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CHMeCONHS(O).sub.2 Me                                                              (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        42 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CHMeCONH.sub.2                                                                     (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        43 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CHMeTz                                                                             (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        44 RS                                                                              7-Cl                                                                              CHCH.sub.2 CH                                                                         SCH.sub.2 CHEtTz                                                                             (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        45 RS                                                                              7-Cl                                                                              CHCH.sub.2 CH                                                                         SCH.sub.2 CHEtCONHS(O).sub.2 CF.sub.3                                                        (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        46 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CHMeNO.sub.2                                                                       (CH.sub.2).sub.2 (7,2-phe)CMe.sub.2 OH        47 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     (CH.sub.2).sub.2 CONHS(O).sub.2 Ph                                                           (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        48 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CHEtCO.sub.2 H                                                                     (CH.sub.2).sub.2 (1,2-phe)CH.sub.2                                            CMe.sub.2 OH                                  49 RS                                                                              7-Cl                                                                              CHCH.sub.2 CH                                                                         SCH.sub.2 CHEtCO.sub.2 H                                                                     (CH.sub.2).sub.3 (1,2-phe)CMe.sub.2 OH        50 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CH(CH.sub.2 CHCH.sub.2)CO.sub.2 H                                                  (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        51 S 7-Cl                                                                              CHCH.sub.2 CH                                                                         SCH.sub. 2 CHEtCO.sub.2 H                                                                    (CH.sub.2).sub.2 (1,2-phe)CHMeOH              52 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CH(CH.sub.2 SMe)CO.sub.2 H                                                         (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        53 S 7-Cl                                                                              CHCH.sub.2 CH                                                                         SCH.sub.2 CH(c-Pr)CO.sub.2 H                                                                 (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        54 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     CH.sub.2 CH(CH.sub.2 CCH)CO.sub.2 H                                                          (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        55 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CHPhCO.sub.2 H                                                                     (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        56 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CHEtCO.sub.2 H                                                                     (1,2-phe)CMe.sub.2 OH                         57 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.2 CMe.sub.2 OH                                                               (1,3-phe)CO.sub.2 H                           58 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.2 CO.sub.2 H                                                                 CH.sub.2 CHOH(1,3-phe)CN4H                    59 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.2 CO.sub.2 H                                                                 CH.sub.2 CHOH(1,4-phe)CN4H                    60 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.2 CO.sub.2 H                                                                 CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH         61 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CHCF.sub.3 CO.sub.2 H                                                              CH.sub. 2).sub.2 (1,2-phe)CMe.sub.2 OH        62 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.3 CO.sub.2 H                                                                 (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        63 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.2 CHMeCO.sub.2 H                                                             (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        64 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(O).sub.2 CH.sub.2 (S)CHEtCO.sub.2 H                                                        (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        65 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CH(CH.sub.2 OMe)CO.sub.2 H                                                         (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        66 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.2 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (1,2-phe)CO.sub.2 H          67 R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.2 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (1,2-phe)CO.sub.2 H          68 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 (S)CHEtCO.sub.2 H                                                                  (CH.sub.2).sub.2 (1,3-phe)CMe.sub.2 OH        69 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CHEtCO.sub.2 H                                                                     (CH.sub.2).sub.2 (7,3-phe)(1,1-c-Bu)OH        70 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.2 CMe.sub.2 OH                                                               (CH.sub.2).sub.3 (1,2-phe)COOH                71 R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.2 CO.sub.2 H                                                                 S(CH.sub.2).sub.2 (1,1-c-Pen)OH               72 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CH(CH.sub.2 CF.sub.3)CO.sub.2 H                                                    (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        73 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.2 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (4-Cl-1,2-phe)CO.sub.2                                       H                                             74 R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 (S)CHEtCONHS(O).sub.2 Me                                                           (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        75 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.2 CMeOH                                                                      (CH.sub.2).sub.2 (1,3-phe)CMe.sub.2                                           CO.sub.2 H                                    76 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.2 CMeOH                                                                      (CH.sub.2).sub.2 (1,3-phe)CHMeCO.sub.2 H      77 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.3 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (1,2-phe)CO.sub.2 H          78 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 (S)CHEtCO.sub.2 H                                                                  (CH.sub.2).sub.2 (1,4-phe)CMe.sub.2 OH        79 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.2 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (1,3-phe)CN.sub.4 H          80 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.3 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (1,2-phe)CHMeCO.sub.2 H      81 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2 ).sub.3 CMe.sub.2 OH                                                              (CH.sub.2).sub.2 (1,2-phe)CHMeCONHS(O).sub                                    .2 CH.sub.3                                   82 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.2 CMe.sub.2 OH                                                               (CH.sub.2).sub.3 (1,2-phe)CO.sub.2 H          83 R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(O).sub.2 CH.sub.2 (S)CHEtCO.sub.2 H                                                        (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        84 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.2 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (4-Cl-1,2-phe)CHMeCO.sub.                                    2 H                                           85 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 (S)CHMeCO.sub.2 H                                                                  (CH.sub.2).sub.2 (1,2-phe)CH.sub.2                                            CMe.sub.2 OH                                  86 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.2 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (7,2-phe)CO.sub.2 Me         87 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.3 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (4-Cl-1,2-phe)CO.sub.2                                       H                                             88 R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.2 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (4-Cl-1,2-phe)CO.sub.2                                       H                                             89 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.3 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2                                           CO.sub.2 H                                    90 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.2 CMe.sub.2 OH                                                               (CH.sub.2).sub. 3 (R)CHMe.sub.2 CO.sub.2                                      H                                             91 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.3 CEt.sub.2 OH                                                               (CH.sub.2).sub.2 (1,2-phe)CO.sub.2 H          92 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.3 CEt.sub.2 OH                                                               (CH.sub.2).sub.2 (1,2-phe)CHMeCO.sub.2 H      93 R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCHMeCH.sub.2 CO.sub.2 H                                                                     (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        94 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.3 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (1,2-phe)CHEtCO.sub.2 H      95 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.3 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (1,2-phe)CH(n-Pr)CO.sub.2                                     H                                            96 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.3 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (1,2-phe)CH(i-Pr)CO.sub.2                                     H                                            97 R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 MeCHMeCO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        98 R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.2 CMe.sub.2 OH                                                               (CH.sub.2).sub.3 (R)CHMeCO.sub.2 H            99 R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 (S)CHMeCN.sub.4 H                                                                  (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        100                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 (S)CHMeCO.sub.2 H                                                                  (CH.sub.2).sub.2 (3-OH-1,4-phe)CHMeOH         101                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.3 CHMeOH                                                                     (CH.sub.2).sub.2 (1,2-phe)CHMeCO.sub.2 H      102                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(S)CHMeCH.sub.2 CO.sub.2 H                                                                  (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        103                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(R)CHMeCH.sub.2 CO.sub.2 H                                                                  (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        104                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(S)CHMe(S)CHMeCO.sub.2 H                                                                    (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        105                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(R)CHMe(R)CHMeCO.sub.2 H                                                                    (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        106                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCHEtCH.sub.2 CO.sub.2 H                                                                     (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        107                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.3 CHMeOH                                                                     (CH.sub.2).sub.2 (1,2-phe)CHEtCO.sub.2 H      108                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 (S)CHMeCO.sub.2 H                                                                  (CH.sub.2).sub.2 (1,2-phe)CH(OH)CH.sub.2                                      (OH)Ph                                        109                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCMe.sub.2 CH.sub.2 CO.sub.2 H                                                               (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        110                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CHMeCH.sub.2 CO.sub.2 H                                                            (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        111                                                                              R 7-Cl                                                                              CH.sub. 2 CMe.sub.2                                                                   SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 H                                                      (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        112                                                                              S 7-Cl                                                                              CMe.sub.2 CH.sub.2                                                                    SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 H                                                      (CH.sub.2).sub.2 (1,2-phe)CO.sub.2 H          113                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.3 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (1,2-phe)(R)CHEtCO.sub.2                                     H                                             114                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.3 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (1,2-phe)(S)CHEtCO.sub.2                                     H                                             115                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.3 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (4-Cl-1,2-phe)CHEtCO.sub.                                    2 H                                           116                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.3 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (1,2-phe)CEt.sub.2                                           CO.sub.2 H                                    117                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.3 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (1,2-phe)CH.sub.2                                            CO.sub.2 H                                    118                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.3 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (1,2-phe)CH(OH)CO.sub.2                                      H                                             119                                                                              S 7-Cl                                                                              CHMeCHMe                                                                              SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 H                                                      (CH.sub.2).sub.2 (1,2-phe)CHEtCO.sub.2 H      120                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.3 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 CMeCH.sub.2 CO.sub.2 H       121                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CMe.sub.2 CH.sub.2 CO.sub.2 H                                                      (CH.sub.2).sub.2 (7,2-phe)CMe.sub.2 OH        122                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.4 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (1,2-phe)CHEtCO.sub.2 H      123                                                                              S 7-F CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CMe.sub.2 CH.sub.2 CO.sub.2 H                                                      (CH.sub.2).sub.2 (1,2-phe)CO.sub.2 H          124                                                                              S 7-Br                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CMe.sub.2 CH.sub.2 CO.sub.2 H                                                      (CH.sub.2).sub.2 (1,2-phe)CO.sub.2 H          125                                                                              S 7-I CH.sub.2 CH.sub.2                                                                     SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 H                                                      (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        126                                                                              S 7-CF.sub.3                                                                        CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CMe.sub.2 CH.sub.2 CO.sub.2 H                                                      (CH.sub.2).sub.2 (1,2-phe)CHMeCO.sub.2 H      127                                                                              S 7-CN                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CMe.sub.2 CH.sub.2 CO.sub.2 H                                                      (CH.sub.2).sub.2 (1,2-phe)CHEtCO.sub.2 H      128                                                                              S 7-NO.sub.2                                                                        CH.sub.2 CH.sub.2                                                                     SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 H                                                      (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        129                                                                              R 7-N.sub.3                                                                         CH.sub.2 CH.sub.2                                                                     SCH.sub.2 (1,1-c-Pr)CH.sub. 2 CO.sub.2 H                                                     (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        130                                                                              RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.2 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 CMe.sub.2 CH.sub.2                                           CO.sub.2 H                                    131                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(1,2-phe)CH.sub.2 CO.sub.2 H                                                                (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        132                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.3 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (1,2-phe)CHEtCO.sub.2 H      133                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.2 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (1,2-phe)CHEtCO.sub.2 H      134                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.3 CMe(4-ClPh)OH                                                              (CH.sub.2).sub.2 (1,2-phe)CHEtCO.sub.2 H      135                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 (1,2-phe)CMe.sub.2 OH                                                              (CH.sub.2).sub.2 CMe.sub.2 CH.sub.2                                           CO.sub.2 H                                    136                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 H                                                      (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        137                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 (1,1-c-Bu)CH.sub.2 CO.sub.2 H                                                      (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        138                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CMe.sub.2 CHMeCO.sub.2 H                                                           (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        139                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 (1,2-phe)CMe.sub.2 OH                                                              (CH.sub.2).sub.2 CMe.sub.2 CH.sub.2                                           CO.sub.2 H                                    140                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCHMeCMe.sub.2 CH.sub.2 CO.sub.2 H                                                           (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        141                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(1,1-c-Pr)CH.sub.2 CO.sub.2 H                                                               (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        142                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(1,1-c-Pr)CHMeCO.sub.2 H                                                                    (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        143                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(1,1-c-Pr)CH.sub.2 CO.sub.2 H                                                               (CH.sub.2).sub.2 (1,3-phe)CMe.sub.2 OH        144                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(1,1-c-Pr)CH.sub.2 CO.sub.2 H                                                               (CH.sub.2).sub.2 (1,2-phe)(1,1-c-Bu)OH        145                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(1,1-c-Pr)CH.sub.2 CO.sub.2 H                                                               (CH.sub.2).sub.2 (1,3-phe)(1,1-c-Bu)OH        146                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 H                                                      (CH.sub.2).sub.2 (1,3-phe)CMe.sub.2 OH        147                                                                              R 7-Cl                                                                              CHCH.sub.2 CH                                                                         SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 H                                                      (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        148                                                                              R 7-Cl                                                                              CHCH.sub.2 CH                                                                         S(1,1-c-Pr)CH.sub.2 CO.sub.2 H                                                               (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        149                                                                              R 7-Cl                                                                              CHCH.sub.2 CH                                                                         SCMe.sub.2 CH.sub.2 CO.sub.2 H                                                               (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        150                                                                              R 7-Cl                                                                              CHCH.sub.2 CH                                                                         S(1,1-c-Pr)(S)CHMeCO.sub.2 H                                                                 (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        151                                                                              R 7-Cl                                                                              CHCH.sub.2 CH                                                                         S(1,1-c-Pr)CHMeCO.sub.2 H                                                                    (CH.sub.2).sub.2 (1,3-phe)CMe.sub.2 OH        152                                                                              R 7-Cl                                                                              CHCH.sub.2 CH                                                                         S(1,1-c-Pr)CH.sub.2 CO.sub.2 H                                                               (CH.sub.2).sub.2 (1,2-phe)(1,1-c-Bu)OH        153                                                                              R 7-Cl                                                                              CHCH.sub.2 CH                                                                         S(1,1-c-Pr)CH.sub.2 CO.sub.2 H                                                               (CH.sub.2).sub.2 (1,3-phe)(1,1-c-Bu)OH        154                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CHEtCO.sub.2 H                                                                     (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        155                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 (1,2-phe)CMe.sub.2 OH                                                              CH.sub.2).sub.2 (1,2-phe)CHEtCO.sub.2 H       156                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.2 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (1,2-phe)CH.sub.2                                            CO.sub.2 H                                    157                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 (1,2-phe)CHMe.sub.2 OH                                                             (CH.sub.2).sub.2 (1,2-phe)CH.sub.2                                            CO.sub.2 H                                    158                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.2 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (4-Cl-1,2-phe)CH.sub.2                                       CO.sub.2 H                                    159                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 (1,2-phe)CMe.sub.2 OH                                                              (CH.sub.2).sub.2 (4-Cl-1,2-phe)CH.sub.2                                       CO.sub.2 H                                    160                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 CMe.sub.2 CH.sub.2 CO.sub.2 H                                                      (CH.sub.2).sub.4 (1,2-phe)CMe.sub.2 OH        161                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     S(CH.sub.2).sub.3 CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (4-Cl-1,2-phe)CH.sub.2                                       CO.sub.2 H                                    162                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                     SCH.sub.2 (1,2-phe)CMe.sub.2 OH                                                              (CH.sub.2).sub.2 (1,1-c-Pr)CH.sub.2                                           CO.sub.2 H                                    __________________________________________________________________________

                                      TABLE II                                    __________________________________________________________________________    ELEMENTAL ANALYSES                                                                             CALCULATED                                                                              FOUND                                              EX.                                                                              FORMULA       C  H   N  C  H   N                                           __________________________________________________________________________    66 C.sub.32 H.sub.33 ClNO.sub.3 SNa.3.5H.sub.2 O                                               60.70                                                                            6.37                                                                              2.21                                                                             60.38                                                                            6.43                                                                              2.44                                        70 C.sub.33 H.sub.35 ClNO.sub.3 SNa.0.5H.sub.2 O                                               66.82                                                                            6.12                                                                              2.36                                                                             66.72                                                                            6.14                                                                              2.19                                        73 C.sub.33 H.sub.32 Cl.sub.2 NO.sub.3 SNa.H.sub.2 O                                           61.73                                                                            5.50                                                                              2.25                                                                             61.97                                                                            5.70                                                                              2.20                                        102                                                                              C.sub.33 H.sub.35 ClNO.sub.3 SNa.H.sub.2 O                                                  65.82                                                                            6.19                                                                              2.33                                                                             66.10                                                                            6.32                                                                              2.16                                        109                                                                              C.sub.34 H.sub.37 ClNO.sub.3 SNa.2.0H.sub.2 O                                               64.39                                                                            6.52                                                                              2.21                                                                             64.31                                                                            6.53                                                                              2.30                                        121                                                                              C.sub.25 H.sub.34 ClNO.sub.3 SNa.1.5H.sub.2 O                                               65.77                                                                            6.42                                                                              2.19                                                                             65.47                                                                            6.14                                                                              2.17                                        136                                                                              C.sub.35 H.sub.37 ClNO.sub.3 SNa.H.sub.2 O                                                  66.98                                                                            6.22                                                                              2.23                                                                             67.31                                                                            6.05                                                                              2.43                                        139                                                                              C.sub.35 H.sub.39 ClNO.sub.3 SNa.1.0H.sub.2 O                                               66.70                                                                            6.56                                                                              2.22                                                                             66.83                                                                            6.50                                                                              2.28                                        142                                                                              C.sub.35 H.sub.37 ClNO.sub.3 SNa.1.5H.sub.2 O                                               66.03                                                                            6.28                                                                              2.20                                                                             66.19                                                                            6.46                                                                              2.60                                        147                                                                              C.sub.36 H.sub.37 ClNO.sub.3 SNa.2.5H.sub.2 O                                               65.00                                                                            6.06                                                                              2.10                                                                             65.43                                                                            6.40                                                                              2.23                                        148                                                                              C.sub.35 H.sub.35 ClNO.sub.3 SNa.1.5H.sub.2 O                                               66.18                                                                            6.03                                                                              2.21                                                                             66.04                                                                            6.13                                                                              2.13                                        150                                                                              C.sub.34 H.sub.33 ClNO.sub.3 SNa.H.sub.2 O                                                  66.71                                                                            5.76                                                                              2.29                                                                             66.17                                                                            5.87                                                                              2.16                                        154                                                                              C.sub.34 H.sub.37 ClNO.sub.3 SNa.3.5H.sub.2 O                                               61.76                                                                            6.70                                                                              2.12                                                                             61.52                                                                            6.54                                                                              1.93                                        158                                                                              C.sub.33 H.sub.34 Cl.sub.2 NO.sub.3 SNa.2.5H.sub.2 O                                        59.73                                                                            5.92                                                                              2.11                                                                             59.77                                                                            5.87                                                                              2.24                                        159                                                                              C.sub.38 H.sub.36 Cl.sub.2 NO.sub.3 SNa.H.sub.2 O                                           65.33                                                                            5.48                                                                              2.00                                                                             65.21                                                                            5.69                                                                              2.03                                        160                                                                              C.sub.37 H.sub.43 ClNO.sub.3 SNa.0.4H.sub.2 O                                               68.64                                                                            6.82                                                                              2.16                                                                             68.62                                                                            6.86                                                                              2.16                                        161                                                                              C.sub.34 H.sub.36 Cl.sub.2 NO.sub.3 SNa.2.0H.sub.2 O                                        61.07                                                                            6.03                                                                              2.09                                                                             61.17                                                                            6.09                                                                              1.92                                        162                                                                              C.sub.35 H.sub.37 ClNO.sub.3 SNa.2.0H.sub.2 O                                               65.05                                                                            6.40                                                                              2.17                                                                             65.45                                                                            6.20                                                                              2.10                                        __________________________________________________________________________

Methods of Synthesis

Compounds of the present invention can be prepared according to thefollowing methods. Temperatures are in degree Celsius.

Method A

Bromo acid II is treated with 2 equivalents of a base such asn-butyllithium in a suitable solvent such as THF at -100° C., then at-78° C. to afford III, which is reacted with IV (see EP 206,751, Dec.30, 1986; EP 318,093, May 31, 1989, and U.S. Pat. No. 4,851,409, Jul.25, 1989) to yield the hydroxyacid V. V is then esterified usingconditions such as methanol/HCl, CH₂ N₂ or MeI/K₂ CO₃ and anorganometallic reagent is then added to give the diol VI. The benzylicalcohol of VI is then reacted with the thiol IX by: (1) making thechloride by reaction with methanesulfonyl chloride in the presence oftriethylamine, and (2) substituting the chloride by the thiol IX in thepresence of a base such as sodium hydride or cesium carbonate to affordVII. In the cases where Q¹ is an ester, hydrolysis with a base such asNaOH, LiOH or K₂ CO₃ (followed by acidification) affords the acid VIII.VII and VIII are both representatives of structure I.

Method B

The ketone IV is reduced to the benzylic alcohol using a reagent such asNaBH₄. This benzylic alcohol is converted to the benzylic bromide, usingconditions such as carbontetrabromide/1,2-bis-(diphenylphosphino)ethane, and treatment withtriphenylphosphine affords the phosphonium salt X. Using a base such aspotassium hexamethyldisilazide, the ylid of X is formed and is added toa lactol. Oxidation of the benzylic alcohol so obtained using conditionssuch as (1) MnO₂ in EtOAc and (2) MnO_(2/) HCN/MeOH affords the esterXI. The thiol IX is then added to XI using a Lewis acid such as AlCl₃ orTiCl₄ to give the thioether XII. Reaction of XII with an organometalliccompound such as a lithium or a magnesium salt, yield, in the caseswhere Q¹ is stable in these conditions, the tertiary alcohol XIII, whichis a representative of structure I.

Method C

The ester XXVII, obtained by Method E, is hydrolyzed with a base such asNaOH to give XIV. XIV is reacted with another organometallic and thereaction mixture is quenched with chlorotrimethyl-silane to yield thehydroxyketone XV. The benzylic alcohol is then reacted withmethanesulfonyl chloride in the presence of a base such astriethylamine. The mesylate so obtained is substituted by the thiolatederivative of IX to afford XVI. Finally, an organometallic reaction or areduction using a reagent such as NaBH₄ on XVI gives the alcohol XVIII.Using this method, two different R groups can be added to give asecondary or an unsymmetrical tertiary alcohol.

Method D

The hydroxyacid XVII (included within the definition of XIV) is cyclizedto the lactone XXI using a reagent such as 2-chloro-N-methylpyridiniumiodide. An organometallic reagent is then added to XXI to give the diolXXII. Finally, the secondary alcohol is substituted by the thiol IX asin Method C to yield the thioether XX.

Method E

The aidehyde XXIII, a derivative of IV, is reacted with anorganometallic reagent and the benzylic alcohol so obtained is oxidizedto XXIV with an oxidant like activated manganese dioxide. XXIV is thenreacted with the iodide XXV in the presence of a base such as lithiumdiisopropylamide to yield the alkylation product XXVI. Reduction withsodium borohydride or addition of an organometallic reagent afford thehydroxyester XXVII, which is then treated as the lactone XXI in Method Dto give the thioether XXVIII.

Method F

The enolate of the ketone XXIX, obtained by treatment of XXIX with abase such as KH or NaH, is reacted with dimethylcarbonate to yield theketoester XXX. XXX is enolized with a base such as NaH and treated withthe iodide XXXI, the methyl ester of XXV. The adduct so obtained is thendecarboxylated using conditions such as heating with HCl in acetic acidto afford a mixture of the ester XXXII and the corresponding acid.Esterification of the mixture, using a reagent such as diazomethane ormethyl iodide and K₂ CO₃, yields XXXII, which is then converted toXXXIII or its epimer, as described in Method G.

Method G

The hydroxy acid XVII is esterified using conditions such as heatingwith MeI and K₂ CO₃ or reacting with diazomethane. Treatment of thishydroxyester with an oxidant such as activated manganese dioxide affordsthe ketoester XXXIV. The ketone is then reduced using the chiraloxazaboro-lidine XXXV in the presence of borane/THF complex. Reactionofthe ester with an organometallic gives the diol XXXVI, which is chiralXXII. Protection of the secondary alcohol withtert-butylchlorodiphenyl-silane in the presence of a base such as4-(dimethyl-amino)pyridine, protection of the tertiary alcohol as the2-tetrahydropyranyl ether and removal of the silyl ether afford XXXVII.The chiral center of XXXVII can be inverted to give XXXVIII usingconditions such as: (1) treatment with triphenyl-phosphine, diethylazodicarboxylate and an acid such as R--(--)α-methoxyphenylacetic acid(chiral acid improves the resolution), and (2) hydrolysis of the esterso obtained with a base such as NaOH. Formation of the mesylate andsubstitution with the thiol IX as in Method C, followed by hydrolysis ofthe 2-tetrahydropyranyl ether using conditions such as pyridiniump-toluenesulfonate in methanol afford the thioethers XXXIXa and XXXIXb.

Method H

The phenylacetic acid XL is reduced to the alcohol XLI using a reagentsuch as borane in tetrahydrofuran. Formation of the alcoholate with oneequivalent of a Grignard reagent, followed by treatment with magnesiumafford the dimagnesium salt of XLI. It is added to a ketone or analdehyde to yield the alcohol XLII. The bromide XLIII is then formedusing conditions such as (1) formation of the mesylate withmethanesulfonyl chloride and triethylamine and (2) substitution of themesylate by sodium bromide in N,N-dimethyl formamide. The dimagnesiumsalt of XLIII is then formed as previously described and added to theketone IV. The adduct XLIV is then-reacted with the thiol IX as inMethod C to yield XLV.

Method I

The ketoester XXX is treated with the iodide XLVI and decarboxylated asin Method F. Reduction of the ketone with a reagent such as NaBH₄ yieldsthe alcohol XLVII. By reaction with an organometallic in toluene, thenitrile XLVII is converted to the amine XLVIII. The thiol IX is thenadded as in Method C to afford XLIX. Reaction of an iodide with theamine XLIX gives a secondary or tertiary amine L. Both XLIX and L arerepresentative of structure I.

Method J

Vinylmagnesium bromide or allylmagnesium bromide is added to theaidehyde derivative of IV to yield LI. Using the procedure of R.C.Larock et al. (Tetrahedron Letters, 30, 6629 (1989)), the aryl halideLII is coupled to the alcohol LI to give LIII. When Q³ is an ester or analcohol, LIII can be converted to LIV or its isomer, a structurerepresentative of Ia, using the procedure of Method G. Also, when Q³ isQ¹, chiral reduction of the ketone LIII with XXXV as in Method Gfollowed by formation of the mesylate and substitution by the thiol LVafford LVI, a structure representative of Ib.

In the following schemata ##STR12##

Assays for Determining Biological Activity

Compounds of Formula I can be tested using the following assays todetermine their mammalian leukotriene antagonist activity and theirability to inhibit leukotriene biosynthesis.

The leukotriene antagonist properties of compounds of the presentinvention were evaluated using the following assays.

LTD₄ Receptor Binding Studies in Guinea Pig Lung Membranes, Guinea PigTrachea and In vivo Studies in Anesthetized Guines Pigs.

A complete description of these three tests is given by T.R. Jones etal., Can. J. Physiol. Pharmacol., 67, 17-28 (1989).

Compounds of Formula I were tested using the following assays todetermine their mammalian leukotriene biosynthesis inhibiting activity.

Determination of Inhibition of 5-Lipoxygenase

The activity of 5-lipoxygenase was measured from the conversion of [¹⁴C]-arachidonic acid to 5-HETE and 5,12-diHETEs catalyzed by the 10,000×gsupernatant fraction from rat PMN leukocytes, using the procedure ofRiendeau and Leblanc (Biochem. Biophys. Res. Comun., 141, 534-540,(1986)) with minor modifications. The incubation mixture contained 25 mMNa⁺ /K⁺ phosphate buffer, pH 7.3, 1 mM ATP, 0.5 mM CaCl₂, 0.5 mMmercaptoethanol and an aliguot of the enzyme preparation in a finalvolume of 0.2 ml. The enzyme was pre-incubated with the inhibitor for 2min at 37° C. before initiation of the reaction with the addition of 2ml of [¹⁴ C]-arachidonic acid (25,000 DPM) in ethanol to obtain a finalconcentration of 10 mM. Inhibitors were added as 500-fold concentratedsolutions in DMSO. After incubation for 10 min at 37° C., the reactionwas stopped by adding 0.8 mL of diethyl ether/methanol/1 M citric acid(30:4:1). The samples were centrifuged at 1,000×g for 5 min and theorganic phases analyzed by TLC on Baker Si250F-PA or Whatman silica gel60A LKGF plates using diethyl ether/petroleum ether/acetic acid(50:50:1) as solvent. The amount of radioactivity migrating at thepositions of arachidonic acid, 5-HETE and 5,12-diHETEs was determinedusing a Berthold TLC analyzer LB 2842. The activity of 5-lipoxygenasewas calculated from the percentage of conversion of arachidonic acid to5-HETE and 5,12-diHETEs after the 10 min incubation.

Human Polymorphonuclear (PMN) Leukocyte LTB₄ Assay

A. Preparation of Human PMN

Human blood was obtained by antecubital venepuncture from consentingvolunteers who had not taken medication within the previous 7 days. Theblood was immediately added to 10% (v/v) trisodium citrate (0.13 M) or5% (v/v) sodium heparin (1000 IU/mL). PMNs were isolated fromanticoagulated blood by dextran sedimentation of erythrocytes followedby centrifugation through Ficoll-Hypaque (specific gravity 1.077), asdescribed by Boyum.¹ Contaminating erythrocytes were removed by lysisfollowing exposure to ammonium chloride (0.16 M) in Tris buffer (pH7.65), and the PMNs resuspended at 5 ×10⁵ cells/mL in HEPES (15mM)-buffered Hanks balanced salt solution containing Ca²⁺ (1.4 mM) andMg²⁺ (0.7 mM), pH 7.4. Viability was assessed by Trypan blue exclusionand was typically greater than 98%.

B. Generation and Radioimmunoassay of LTB₄

PMNs (0.5 mL; 2.5×10⁵ cells) were placed in plastic tubes and incubated(37° C., 2 min) with test compounds at the desired concentration orvehicle (DMSO, final concentration 0.2%) as control. The synthesis ofLTB₄ was initiated by the addition of calcium ionophore A23187 (finalconcentration 10 mM) or vehicle in control samples and allowed toproceed for 5 minutes at 37° C. The reactions were then terminated bythe addition of cold methanol (0.25 mL) and samples of the entire PMNreaction mixture were removed for radioimmunoassay of LTB₄.

Samples (50 mL) of authentic LTB₄ of known concentration inradioimmunoassay buffer (RIA) buffer (potassium phosphate 1 mM; disodiumEDTA 0.1 mM; Thimerosal 0.025 mM; gelatin 0.1%, pH 7.3) or PMN reactionmixture diluted 1:1 with RIA buffer were added to reaction tubes.Thereafter [³ H]-LTB₄ (10 nCi in 100 mL RIA buffer) and LTB4-antiserum(100 mL of a 1:3000 dilution in RIA buffer) were added and the tubesvortexed. Reactants were allowed to equilibrate by incubation overnightat 4° C. To separate antibody-bound from free LTB₄, aliquots (50 mL) ofactivated charcoal (3% activated charcoal in RIA buffer containing 0.25%Dextran T-70) were added, the tubes vortexed, and allowed to stand atroom temperature for 10 minutes prior to centrifugation (1500×g; 10 min;4° C.). The supernatants containing antibody-bound LTB₄ were decantedinto vials and Aquasol 2 (4 mL) was added. Radioactivity was quantifiedby liquid scintillation spectrometry. Preliminary studies establishedthat the amount of methanol carried into the radioimmuno-assay did notinfluence the results. The specificity of the antiserum and thesensitivity of the procedure have been described by Rokach et al.² Theamount of LTB₄ produced in test and control (approx. 20 ng/10⁶ cells)samples were calculated. Inhibitory dose-response curves wereconstructed using a four-parameter algorithm and from these the IC₅₀values were determined.

Compounds of Formula I were tested in the following assays to determinetheir in vivo activity as both leukotriene antagonist and leukotrienebiosynthesis inhibitor.

(1) Boyum, A. Scand. J. Clin. Lab. Invest., (21 (Supp 97), 77 (1968).

(2) Rokach, J.; Hayes, E.C.; Girard, Y.; Lombardo,

D.L.; Maycock, A.L.; Rosenthal, A.S.; Young,

R.N.; Zamboni, R.; Zweerink, H.J. Prostalglandins Leukotrienes andMedicine, 13, 21 (1984).

Asthmatic Rat Assay

Rats are obtained from an inbred line of asthmatic rats. Both female(190-250 g) and male (260-400 g) rats are used.

Egg albumin (EA), grade V, crystallized and lyophilized, is obtainedfrom Sigma Chemical Co., St. Louis. Aluminum hydroxide is obtained fromthe Regis Chemical Company, Chicago. Methysergide bimaleate was suppliedby Sandoz Ltd., Basel.

The challenge and subsequent respiratory recordings are carried out in aclear plastic box with internal dimensions 10×6×4 inches. The top of thebox is removable; in use, it is held firmly in place by four clamps andan airtight seal is maintained by a soft rubber gasket. Through thecenter of each end of the chamber a Devilhiss nebulizer (No. 40) isinserted via an airtight seal and each end of the box also has anoutlet. A Fleisch No. 0000 pneumotachograph is inserted into one end ofthe box and coupled to a Grass volumetric pressure transducer (PT5-A)which is then connected to a Beckman Type R Dynograph throughappropriate couplers. While aerosolizing the antigen, the outlets areopen and the pneumotachograph is isolated from the chamber. The outletsare closed and the pneumotachograph and the chamber are connected duringthe recording of the respiratory patterns. For challenge, 2 mL of a 3%solution of antigen in saline is placed into each nebulizer and theaerosol is generated with air from a small Potter diaphragm pumpoperating at 10 psi and a flow of 8 liters/minute.

Rats are sensitized by injecting (subcutaneously) 1 mL of a suspensioncontaining 1 mg EA and 200 mg aluminum hydroxide in saline. They areused between days 12 and 24 postsensitization. In order to eliminate theserotonin component of the response, rats are pretreated intravenously 5minutes prior to aerosol challenge with 3.0 mgm/kg of methysergide. Ratsare then exposed to an aerosol of 3% EA in saline for exactly 1 minute,then their respiratory profiles are recorded for a further 30 minutes.The duration of continuous dyspnea is measured from the respiratoryrecordings.

Compounds are generally administered either orally 1-4 hours prior tochallenge or intravenously 2 minutes prior to challenge. They are eitherdissolved in saline or 1% methocel or suspended in 1% methocel. Thevolume injected is 1 mL/kg (intravenously) or 10 mL/kg (orally). Priorto oral treatment rats are starved overnight. Their activity isdetermined in terms of their ability to decrease the duration ofsymptoms of dyspnea in comparison with a group of vehicle-treatedcontrols. Usually, a compound is evaluated at a series of doses and anED₅₀ is determined. This is defined as the dose (mg/kg) which wouldinhibit the duration of symptoms by 50%.

Pulmonary Mechanics in Trained Conscious Squirrel Monkeys

The test procedure involves placing trained squirrel monkeys in chairsin aerosol exposure chambers. For control purposes, pulmonary mechanicsmeasurements of respiratory parameters are recorded for a period ofabout 30 minutes to establish each monkey's normal control values forthat day. For oral administration, compounds are dissolved or suspendedin a 1% methocel solution (methylcellulose, 65HG,400 cps) and given in avolume of 1 ml/kg body weight. For aerosol administraiton of compounds,a DeVilbiss ultrasonic nebulizer is utilized. Pretreatment periods varyfrom 5 minutes to 4 hours before the monkeys are challenged with aerosoldoses of either leukotriene D₄ (LTD₄) or Ascaris antigen.

Following challenge, each minute of data is calculated by computer as apercent change from control values for each respiratory parameterincluding airway resistance (R_(L)) and dynamic compliance (C_(dyn)).The results for each test compound are subsequently obtained for aminimum period of 60 minutes post challenge which are then compared topreviously obtained historical baseline control values for that monkey.In addition, the overall values for 60 minutes post-challenge for eachmonkey (historical baseline values and test values) are averagedseparately and are used to calculate the overall percent inhibition ofLTD₄ or Ascaris antigen response by the test compound. For statisticalanalysis, paired t-test is used. (References: McFarlane, C.S. et al.,Prostaglandins, 28, 173-182 (1984) and McFarlane, C.S. et al., AgentsActions, 22, 63-68 (1987)).

Prevention of Induced Bronchoconstriction in Allergic Sheep

A. Rationle:

Certain allergic sheep with known sensitivity to a specific antigen(Ascaris suum) respond to inhalation challenge with acute and latebronchial responses. The time course of both the acute and the latebronchial responses approximates the time course observed in asthmaticsand the pharmacological modification of both responses is similar tothat found in man. The effects of antigen in these sheep are largelyobserved in the large airways and are conveniently monitored as changesin lung resistance or specific lung resistance.

B. Methods:

Animal Preparation: Adult sheep with a mean weight of 35 kg (range, 18to 50 kg) are used. All animals used meet two criteria: a) they have anatural cutaneous reaction to 1:1,000 or 1:10,000 dilutions of Ascarissuum extract (Greet Diagnostics, Lenois, NC) and b) they have previouslyresponded to inhalation challenge with Ascaris suum with both an acutebronchoconstriction and a late bronchial obstruction (Abraham, W.M.,Delehunt, J.C., Yerger, L. and Marchette, B., Am. Rev. Resp. Dis., 128,839-44 (1983)).

Measurement of Airway Mechanics: The unsedated sheep are restrained in acart in the prone position with their heads immobilized. After topicalanesthesia of the nasal passages with 2% lidocaine solution, a ballooncatheter is advanced through one nostril into the lower esophagus. Theanimals are then intubated with a cuffed endotracheal tube through theother nostril using a flexible fiberoptic bronchoscope as a guide.Pleural pressure is estimated with the esophageal balloon catheter(filled with one ml of air), which is positioned such that inspirationproduces a negative pressure deflection with clearly discerniblecardiogenic oscillations. Lateral pressure in the trachea is measuredwith a sidehole catheter (inner dimensions, 2.5 man) advanced throughand positioned distal to the tip of the nasotracheal tube.Transpulmonary pressure, the difference between tracheal pressure andpleural pressure, is measured with a differential pressure transducer(DP45; Validyne Corp., Northridge, Calif.). Testing of the pressuretransducer catheter system reveals no phase shift between pressure andflow to a frequency of 9 Hz. For the measurement of pulmonary resistance(R_(L)), the maximal end of the nasotracheal tube is connected to apneumotachograph (Fleisch, Dyna Sciences, Blue Bell, Pa). The signals offlow and transpulmonary pressure are recorded on an oscilloscope (ModelDR-12; Electronics for Medicine, White Plains, N.Y.) which is linked toa PDP-11 Digital computer (Digital Equipment Corp., Maynard, Mass.) foron-line calculation of R_(L) from transpulmonary pressure, respiratoryvolume obtained by integration and flow. Analysis of 10-15 breaths isused for the determination of R_(L). Thoracic gas volume (V_(tg)) ismeasured in a body plethysmograph, to obtain specific pulmonaryresistance (SR_(L) =R_(L) •V_(tg)).

Aerosol Delivery Systems: Aerosols of Ascarie suum extract (1:20) aregenerated using a disposable medical nebulizer (Raindrop®, PuritanBennett), which produces an aerosol with a mass median aerodynamicdiameter of 6.2 μM (geometric standard deviation, 2.1) as determined byan electric size analyzer (Model 3030; Thermal Systems, St. Paul,Minn.). The output from the nebulizer is directed into a plastict-piece, one end of which is attached to the nasotracheal tube, theother end of which is connected to the inspiratory part of a Harvardrespirator. The aerosol is delivered at a tidal volume of 500 ml of arate of 20 per minute. Thus, each sheep receives an equivalent dose ofantigen in both placebo and drug trials.

Experimental Protocol: Prior to antigen challenge baseline measurementsof SR_(L) are obtained, infusion of the test compound is started 1 hrprior to challenge, the measurement of SR_(L) repeated and then thesheep undergoes inhalation challenge with Ascaris suum antigen.Measurements of SR_(L) are obtained immediately after antigen challengeand at 1,2,3,4,5,6,6.5,7,7.5 and 8 hr after antigen challenge. Placeboand drug tests are separated by at least 14 days. In a further study,sheep are given a bolus dose of the test compound followed by aninfusion of the test compound for 0.5-1 hr prior to ascaris challengeand for 8 hr after ascaris as described above.

Statistical Analysis: A Kruskal-Wallis one way ANOVA test was used tocompare the acute immediate responses to antigen and the peak lateresponse in the controls and the drug treated animals.

The invention is further defined by reference to the following examples,which are intended to be illustrative and not limiting. All temperaturesare in degrees Celsius.

EXAMPLE 13

Sodium 3-((1-(3-(2-(7-chloro-2-quinolinyl)ethyl)-phenyl)-3-(2-(2-hydroxy-2- propyl)phenyl)propyl)thio)-2-methylpropanoate

Step 1: Ethyl 3-(acetyllthio)-2-methylpropanoate

Ethyl 2-methylpropenoate (39 mmol) was diluted with 5.6 mL (78 mmol) ofthiolacetic acid and stirred at 65° C. for 36 h. The mixture was thendiluted with ether, washed with water and the organic phase was driedwith Na₂ SO₄. Evaporation to dryness yielded the title material as anorange oil which was used as such for the next step.

Step 2: Ethyl 3-mercapto-2-methylpropanoate

At -20° C., 3N NaOH (150 mL, 450 mmol) was added dropwise to a solutionof ethyl 3-(acetyl-thio)-2-methylpropanoate (66.47 g, 349 mmol, Step 1)in 700 mL of MeOH and the mixture was stirred at that temperature for 30min. 25% Aq NH₄ OAc was then added and the title thiol was extractedwith EtOAc, dried over MgSO₄, concentrated and distilled to yield 42.52g (82%) of the title compound as an oil; bp: 96-98° C./15 mmHg. ¹ H NMR(CDC13): δ1.21-1.36 (6H, m), 1.50 (1H, t, SH), 2.66 (2H, m), 2.81 (1H,m), 4.19 (2H, q).

Step 3: 3- Mercapto-2- methylpropanoic acid

A mixture of the ester of Step 2 (6.67 mmol) and 1.0N NaOH (13 mL) in 55mL of MeOH:THF 3:2 was stirred at r.t. for 24 h. 25% Aq NH₄ OAc was thenadded and the mixture was acidified with HOAc. The title acid wasextracted with EtOAc and dried over Na₂ SO₄. Kugelrohr distillation at100° C./15 mm Hg yielded the title compound as a colorless oil. ¹ H NMR(CDC13): δ1.30 (3H, d), 1.58 (1H, t), 2.8 (3H, m), 10.3 (1H, very br s).

Step 4: 3-((1-(3-(2-(7-chloro-2-quinolinyl)ethyl)-phenyl)3; -(2-(methoxycarbonyl) phenyl)propyl)-thio)2-methylpropanoic acid

At -10° C., AlCl₃ (2.437 g, 18.3 mmol) was added to a solution of methyl2-(3-(3-(2-(7-chloro-2-quinolinyl)ethyl)phenyl)-2-propenyl)benzoate (EP318,093, May 31, 1989, Example 36, Step 1) (1.013 g, 2.28 mmol) and3-mercapto-2-methylpropanoic acid (356 mg, 2.96 mmol (Step 3) in 25 mLof CH₂ Cl₂ and the mixture was stirred at 0° C. in the dark for 2 h.Cold aq NH₄ OAc, EtOAc an THF were then added and the mixture wasstirred until complete dissolution of the oil. The product was extractedwith EtOAc:THF 1:1, dried over Na₂ SO₄ and concentrated. The sodium saltof the acid was formed in EtOH with 500 μL of 10N NaOH. It was purifiedon an Amberlite ion exchange resin XAD-8. Elution with water separatedthe sodium 3-mercapto-2-methylpropanoate and elution with methanolafforded the title acid as an impure sodium salt. The compound wasdissolved in saturated aq NH₄ Cl, extracted with EtOAc:THF 1:1, driedover Na₂ SO₄ and purified by flash chromatography on silica usingacetone:toluene:HOAc 5:95:1 to yield 766 mg (60%) of the title acid.

Step 5:3-((1-(3-(2-(7-chloro-2-quinolinyl)ethyl)-phenyl)3-(2-(2-(hydroxy-2-propyl)phenyl)-propl)thio)-2-methylpropanoic acid

To the ester of Step 4 (626 mg, 1.11 mmol) dissolved in 10 mL of THF at0° C., 1.5 M MeMgBr (4.0 mL, 6.0 mmol) was added slowly and the mixturewas stirred at 0° C. for 2 h and at r.t. for 2 h. At 0° C., aq saturatedNH₄ Cl was added and the product was extracted with EtOAc, dried overNa₂ SO₄ and purified by flash chromatography on silica usingacetone:toluene:HOAc 5:95:1 and 7.5:92.5:1. The pure title compound wasfinally obtained by HPLC on a μ-Porasil column (diameter: 12 mm; flowrate: 8.9 ml min⁻¹) using acetone:toluene:HOAc 5:95:1. Yield: 246 mE,39%.

Step 6:

To the acid of Step 5 (243 mg, 431 mmol) in 10 mL of EtOH was added 1.0N NaOH (430 μl ). The solvents were evaporated and the product wasfreeze-dried to give 250 mg of the title compound as a yellowish solid.Anal. calcd for C₃₃ H₃₅ NO₃ ScClNa•l.5H₂ O: C, 64.85; H, 6.27; N, 2.29.Found: C, 64.29; H, 6.26; N, 2.21.

EXAMPLE 14

Sodium3-((1-(3-(2-(7-chloro-2-quinolinyl)ethyl)phenyl-phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)propyl)thio)-propanoate

Step 1: Methyl 3-((1-(3-(2-(7-chloro-2-quinolinyl)-ethyl)phenyl)-3-(2-(methoxycarbonyl)phenyl)-propyl)thio)proanoate

Using the procedure of Example 13, Step 4, but avoiding the purificationon ion exchange resin, methyl 3-mercaptopropanoate was added to methyl2-(3-(3-(2-(7-chloro-2-quinolinyl)ethyl)phenyl)-2-propenyl)benzoate(Example 13, Step 4) to give the title compound in 77% yield. ¹ H NMR(CD₃ COCD₃): δ2.08 (2H, m), 2.45 (411, m), 2.75 (1H, m), 2.90 (1H, m),3.20 (2H, m), 3.30 (211, m), 3.60 (3H, s), 3.82 (3H, s), 3.88 (1H, dd),7.15-7.33 (6H, m), 7.38-7.50 (3H, m), 7.84 (1H, d), 7.87 (1H, d), 7.98(1H, br s), 8.20 (1H, d).

Step 2:3-((1-(3-(2-(7-chloro-2-quinolinyl)ethyl)-phenyl)-3-(2-(methoxycarboxyl)phenyl)propyl)-thio)propanoic acid

The diester of Step 1 (875 mg, 1.56 mmol) was dissolved in 75 mL of MeOHand 7.5 mL of THF. At room temperature, aqueous 1M K₂ CO₃ (15 mL, 15mmol) was added and the mixture was stirred overnight. The mixture wasconcentrated under reduced pressure and then neutralized with HCl1M andsaturated aqueous NH₄ Cl until pH=5-6. The acid ester was extracted withEtOAc (3×20 mL) and the organic phase was dried over MgSO₄, filtered andevaporated to give an oil. Purification by flash chromatography onsilica gel with EtOAc:Toluene:Acetone:HCOOH (10:83:7:0.2) yielded 605 mg(71% yield) of the title compound. ¹ H NMR (CD₃ COCD₃): δ2.08 (2H, m),2.46 (4H, m), 2.75 (1H, m), 2.90 (1H, m), 3.18 (2H, m), 3.30 (2H, m),3.80 (3H, s), 3.90 (1H, dd), 7.15-7.32 (6H, m), 7.38-7.50 (3H, m), 7.82(1H, d), 7.87 (1H, d), 8.0 (1H, br s), 8.19 (1H, d).

Step 3

The acid ester of Step 2 was converted to the tertiary alcohol as inExample 13, Step 5. This alcohol was purified as thet-butyldiphenylsilyl ester. The formation of the silyl ester waseffected with t-butyldiphenylsilyl chloride, triethylamine and4-dimethylaminopyridine in CH₂ Cl₂. Hydrolysis was done withtetrabutylammonium fluoride in HOAc and THF. Finally, the title compoundwas obtained as in Example 13, Step 6. Anal. calcd for C₃₂ H₃₃ NO₃SClNa•0.5H₂ O: C, 66.37; H, 5.92; N, 2.42. Found: C, 66.15; H, 5.62; N,2.24.

EXAMPLE 73

2-(3-(S)-(3-(2-(7-chloro-2-quinolinyl)ethyl)phenyl)-3-((3-hydroxy-3-methylbutyl)thio)propyl )-5-chloro-benzoic acid

The title compound was prepared according to Example 158, but usingmethyl 2-bromo-5-chlorobenzoate.

EXAMPLE 102

3-(S)-((l(R)-(3-(2-(7-chloro-2-quinolinyl)ethyl)-phenyl-3-(2-(2-hydroxy-2-propyl)phenyl)propyl)thio)butanoic acid

Step 1: Methyl 3(S)-(acetylthio)butanoate

To a -23° C. solution of PPh₃ (40 mmol, 10.48 g) in THF (100 mL) wasadded DEAD (diethylazodicarboxylate) (40 mmol, 6.28 mL) dropwise and themixture was stirred at -23° C. for 16 h, during which time a whiteprecipitate was obtained. A THF (30 mL) solution of methyl3(R)-hydroxybutyrate (20 mmol, 2.36 g) and thiolacetic acid (40 mmol,2.85 mL) was slowly added and the mixture was allowed to slowly warm to25° C. and was stirred 16 h at 25° C. Most of the THF was removed invacuo and EtOAc (10 mL) and hexanes (100 mL) were added. Insolubles wereremoved by filtration and the residue was purified by chromatography onsilica gel to afford the title compound (yield: 45%). [α]_(D) ²⁵ =-21 °(c=3, CHCl₃ ). ¹ H NMR (acetone d₆) δ1.30 (3H, d), 2.25 (3H, s),2.45-2.80 (2H, m), 3.62 (3H, s), 3.75-3.95 (1H, m).

Step 2:

The title compound was prepared according to Method J, starting from3-(2-(7-chloro-2-quino-linyl)ethyl)benzaldehyde (Example 158) and methyl3(S)-mercaptobutanoate, obtained by reaction of methyl3(S)-(acetylthio)butanoate with hydrazine in MeCN to deprotect thethiol.

EXAMPLE 10

3-((1(R)-(3-(2-(7-chloro-2-quino-linyl)ethyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)propyl)thio)-3-methylbutanoic acid

Step, 1: 3-Benzylthio-3-methylbutanoic acid

A solution of 3,3-dimethylacrylic acid (7 g, 70 mmol) and benzylmercaptan (8.9 mL, 7.5 mmol) in piperidine (70 mL) was heated to refluxfor 2 days. The piperidine was then evaporated and the product waspartitioned between EtOAc and an aqueous solution of 1N HCl. The organicphase was washed with brine and dried over MgSO₄. After evaporation ofthe solvent the product was distilled with a Kugelrohr apparatus underhigh vacuum (1 mmHg) to give 15.5 g of the title compound (99% yield). ¹H NMR (CDCl₁₃) δ1.50 (6H, s), 2.67 (2H, s), 3.82 (2H, s), 7.30 (SH, m).

Step 2: 3-Mercapto-3l -methylbutanoic acid

Approximately 300 mL of NH₃ was condensed in a three-neck flaskmaintained at -70° C. Then, 8.3 g of Na (0.35 mol) was added in smallpieces and with very vigorous stirring. The3-benzylthio-3-methylbutanoic acid from Step 1 (15.5 g, 69 mmol)dissolved in THF (50 mL) was added dropwise at -78° C. The deep bluesolution was stirred for 1 h at -78° C. and solid NH₄ Cl and an aqueoussolution of NH₄ Cl was added until the blue color vanished. The solutionwas then warmed to room temperature and the ammonia was evaporated witha stream of nitrogen. The reaction mixture was then acidified with HOAc,extracted with EtOAc, washed with brine and dried over MgSO₄. Thesolvent was evaporated and the residual oil was used without furtherpurification. ¹ H NMR (CDC13) δ1.50 (6H, s), 2.38 (1H, s) and 2.72 (2H,s).

Step 3:

The title compound was prepared according to Example 102, but using3-mercapto-3-methyl butanoic acid.

EXAMPLE 121

4-((1 (R)-(3-(2-(7-chloro-2-quinolinyl)ethyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)propyl)thio)-3,3-dimethylbutanoic acid

Step 1: Methyl 3,3-dimethyl-4-hydroxybutanoiate

To a suspension of LAH (lithium aluminum hydride) (4.9 g, 0.129 mol) inTHF (300 mL) maintained at -78° C. was slowly added (45 min) a solutionof 2,2-dimethylsuccinic anhydride (16.5 g, 0.129 mol) in THF (350 mL).After 45 min of vigorous stirring the reaction mixture was warmed to-60° C. and poured into 1 M aqueous sodium potassium tartrate (500 mL)and stirred for 2 h at r.t. The mixture was then acidified with HOAc(150 mL) and extracted three times with EtOAc. The combined organicphases were washed with brine and dried over Na₂ SO₄. The residual oilwas dissolved in Et₂ O and a solution of diazomethane in Et₂ O (about300 mL, 0.15 mol) was added until the yellow color remained. An aqueoussolution of NH₄ Cl was added and the ester was extracted with Et0Ac anddried over MgSO₄. The oil was purified by flash chromatography with 2:3EtOAc:hexane to yield the title compound (13.5 g, 72%). ¹ H NMR (CDC13)δ1.00 (6H, s), 2.33 (3H, br s), 3.42 (2H, s), 3.70 (3H, s).

Step 2: Methyl 4-(acetylthio)-3,3-dimethylbutanoate

To a solution of PPh₃ (107.8 g, 0.411 mol) in THF (700 mL) maintained at0° C. was added dropwise DEAD (64.7 mL, 0.411 mol) and the mixture wasstirred at 0° C. for 30 min until the complex was precipitated. Asolution of the alcohol of Step 1 (30 g, 0.205 mol) and thiolacetic acid(29.4 mL, 0.411 mol) in THF (300 mL) was then added dropwise (mechanicalstirring). After 4 days at 4° C. the reaction mixture was evaporated todryness, the white precipitate was suspended in 30:1 hexane:EtOAc andfiltered. The residual oil was then purified by a flash chromatographyusing toluene then 100:1 toluene:EtOAc to yield the title compound.Yield: 31 g, 74%. ¹ H NMR (CDCl₃) δ1.05 (6H, s), 2.27 (2H, s), 2.37 (3H,s), 3.00 (2H, s), 3.65 (3H, s).

Step 3:

The title compound was prepared according to Example 102, but usingmethyl 3,3-dimethyl-4-mercapto-butanoate obtained by hydrazine treatmentof methyl 3,3-d imethyl-4-(acetylthio) butanoate.

EXAMPLE 136

1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethyl)phenyl)-3-(2-(2-hydroxy-2-propyl) phenyl)propyl)thio)methyl)-cycylopropaneacetic acid

Step 1: 1,1-cyclopropanedimethanol

A solution of LiAlH₄ (50 g, 1.32 mol) in 1.6 L of THF was cooled to -18°C. under N₂. A solution of diethyl 1,1-cyclopropanedicarboxylate (175 g,0.94 mol) in 1.2 L of THF was then added dropwise over 50 min, at such arate that the internal temperature of the reaction remained below 10° C.The cooling bath was then removed, and after 15 min, the temperaturereached 15° C. The reaction was then quenched by careful addition of 50mL H₂ O, followed by 50 mL of 15% NaOH, and then 150 mL of H₂ O. Afterthe mixture turned white, it was filtered through celite and the bed waswashed with 4 L of THF. Evaporation gave an oil which was distilled togive 81 g (0.79 mol, 84%) of the title compound as a colorless oil, b.p.131-138° C./15 mmHg. ¹ H NMR (CDCl₃) δ0.48 (4H, s), 3.30 (2H, s), 3.58(4H, s).

Step 2: 1-(hydroxymethyl)cyclopropanemethyl benzoate

To a solution of the diol of Step 1 (81 g, 0.79 mol) and pyridine (96mL, 1.19 mol) in CH₂ Cl₂ (1 L) cooled at 0° C. was added slowly benzoylchloride (121 mL, 1.03 mol). The reaction mixture was warmed to r.t.overnight and then poured into an aqueous solution of NH₄ Cl. Theproducts were extracted in CH₂ Cl₂, washed with brine and dried over Na₂SO₄. The residual oil was purified by flash chromatography with 2:1hexane:EtOAc and then 1:2 hexane:EtOAc to yield first, 116 g (47% yield)of the diester, then 89 g (54% yield) of the title alcohol. ¹ H NMR(CDCl₃) δ0.65 (4H, m), 2.20 (1H, t), 3.53 (2H, d), 4.35 (2H, s), 7.45(2H, m), 7.60 (1H, m), 8.07 (2H, m).

Step 3: 1-(benzoyloxymethyl)cyclopropaneacetonitrile

To a solution of the alcohol of Step 2 (80 g, 0.388 mol) and Et₃ N (162mL, 1.16 mol) in CH₂ Cl₂ (1.5 L) cooled at -40° C. was addedmethanesulfonyl chloride (75 mL, 0.504 mol). The reaction mixture waswarmed to -10° C. for 20 min and then poured into an aqueous solution ofNaHCO₃ and extracted with CH₂ Cl₂. The organic phases were washed withbrine and dried over Na₂ SO₄. The residual oil was then dissolved inDMSO (1.5 L) and NaCN was added (86 g, 1.76 mol) portionwise. Thereaction mixture was stirred at r.t. for 3 days then poured in anaqueous solution of NaHCO₃ and extracted with Et₂ O. The organic phaseswere washed with brine and dried over Na₂ SO₄. Evaporation of thesolvent afforded the title product. ¹ H NMI (CDCl₃) δ0.80 (4H, m), 2.62(2H, s), 4.27 (2H, s), 7.48 (2H, m), 7.60 (1H, m), 8.08 (2H, m).

Step 4: Methyl 1-(hydroxymethyl)cyclopropaneacetate

The nitrile of Step 3 (0.388 mol) was dissolved in ethanol (400 mL), 8NKOH (800 mL) was added and the reaction mixture was heated to refluxovernight. Most of the ethanol was evaporated and ice was added to themixture. Concentrated HCl was added (600 mL) dropwise at 0° C. (withoutwarming over 10° C. inside the solution) until obtention of pHapprox. 1. The acid was then extracted with EtOAc two times and theorganic phases were washed 2 times with brine and dried over Na₂ SO₄.The solvent was evaporated and the solid was dissolved in THF (500 mL).A solution of diazomethane in Et₂ O (about 1.7 L, 0.85 mol) was added at0° C. until the yellow color remained and no more acid could be seen byTLC. The solvent was evaporated and the residual oil was purified byflash chromatography using 1:1 to 2:1 EtOAc:hexane to yield 28.2 g, (50%yield) of the title compound. ¹ H NMR (CDCl₃) δ0.55 (4H, m), 2.45 (2H,s), 2.55 (1H, t), 3.5 (2H, d), 3.70 (3H, s).

Step 5: Methyl 1-(acetylthiomethyl)cyclopropane-acetate

To a solution of the alcohol of Step 4 (28.2 g, 0.20 mol) and Et₃ N (82mL, 0.59 mol) in CH₂ Cl₂ (1 L) cooled to -40° C. was addedmethanesulfonyl chloride (43.5 mL, 0.3 mol). The reaction mixture waswarmed to -10° C. for 20 min and then an aqueous solution of NaHC03 wasadded. The product was extracted with CH₂ Cl₂, washed with brine anddried over Na₂ SO₄. A portion of this mesylate (0.053 mol) was thendissolved in DMF (180 mL) and cooled to 0° C. Freshly prepared cesiumthiol acetate (J. Org. Chem., 51, 3664, (1986)) (22 g, 0.11 mol) wasadded and the mixture was stirred overnight at r.t. The reaction mixturewas poured into an aqueous solution of NaHCO₃ and extracted with Et₂ O.The organic phases were washed with brine and dried over Na₂ SO₄. Theresidual oil was then purified by flash chromatography with 10:1hexane:EtOAc to yield 7.5 g, 70%, of the title compound. ¹ H NMR (CDCl₃)δ0.60 (4H, m), 2.30 (2H, s), 2.35 (3H, s), 3.03 (2H, s), 3.70 (3H, s).

Step 6:

The title compound was prepared according to Example 102, but usingmethyl 1-(mercaptomethyl )cyclo-propaneacetate, generated by hydrazinetreatment of methyl 1-(acetylthiomethyl )cyclopropaneacetate.

EXAMPLE 141

1-((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)propyl)thio)cycl-propaneacetic acid

Step 1: Methyl 1-(acetylthio)cyclopropaneacetate

A solution of 8.7 g of methyl cyclopropylidene acetate (TetrahedronLett. 1986, 27, 1281) in 11.1 mL of thioacetic acid was heated at 85° C.for 2 h and then distilled with a Vigreux column to give an orange oil,b.p. 90° C./250 mmHg. The title compound was obtained by flashchromatography of this orange oil with 5:1 hexane:EtOAc, to give acolorless oil. ¹ H NMR (CDCl₃) δ1.00 (4H, two m), 2.28 (3H, s), 2.65(21t, s) and 3.70 (3H, s).

Step 2:

The title compound was prepared according to Example 102, but usingmethyl 1-mercaptocyclopropane-acetate, generated from methyl1-(acetylthio)cyclo-propaneacetate.

EXAMPLE 158

2-(3-(S)-(3-(2-(7-chloro-2-quinolinyl)ethyl)phenyl)-3-((3-hydroxy-3-methylbutyl)thio) propyl)-5-chlorophenylacetic acid

The title compound was prepared according to Method J, with3-(2-(7-chloro-2-quinolinyl)ethyl)-benzaldehyde, methyl2-bromo-5-chlorophenyl acetate, and 3-hydroxy-3-methyl butanethiol asstarting materials. 3-(2-(7-chloro-2-quinolinyl)ethyl)-benzaldehyde wasprepared by, first, deprotonation of 7-chloro-2-quinaldine with lithiumdiisopropylamide and alkylation with 3-cyanobenzyl bromide, followed byreduction of the nitrile with DIBAL in toluene.

3-hydroxy-3-methylbutanethiol was prepared by reacting MeMgBr on methyl3-mercapto propanoate.

What is claimed is:
 1. A compound of the formula: ##STR13## wherein: R¹is H, halogen, --CF₃, --CN, --NO₂, or N₃ ;R² is lower alkyl, loweralkenyl, lower alkynyl, --F₃, --CH₂ F, --CHF₂, --CH₂ CF₃, substituted orunsubstituted phenyl, substituted or unsubstituted benzyl, substitutedor unsubstituted 2-phenethyl, or two R² groups joined to the same carbonmay form a ring of up to 8 members containing 0-2 heteroatoms chosenfrom O, S, and N; R³ is Hor R² ; R⁴ is halogen, --NO₂, --CN, --OR³,--SR³, NR³ R³, NR³ C(O)R⁷ or R³ ; R⁵ is H, halogen, --NO₂, --N₃, --CN,--SR², --NR³ R³, --OR³, lower alkyl, or --C(O)R³ ; R⁶ is --(CH₂)_(s)--C(R⁷ R⁷)--(CH₂)_(s) --R⁸ or --CH₂ C(O)NR¹² R¹² ; R⁷ is H or C₁ -C₄alkyl; R⁸ is A) a monocyclic or bicyclic heterocyclic radical containingfrom 3 to 12 nuclear carbon atoms and 1 or 2 nuclear heteroatomsselected from N, S or O and with each ring in the heterocyclic radicalbeing formed of 5 or 6 atoms, or B) the radical W-R⁹ ; R⁹ contains up to20 carbon atoms and is (1) an alkyl group or (2) an alkylcarbonyl groupof an organic acyclic or monocyclic carboxylic acid containing not morethan 1 heteroatom in the ring; R¹⁰ is --SR¹¹, --OR¹², or --NR¹² R¹² ;R¹¹ is lower alkyl, --C(O)R¹⁴, unsubstituted phenyl, or unsubstitutedbenzyl; R¹² is H, R¹¹, or two R¹² groups joined to the same N may form aring of 5 or 6 members containing 1-2 heteroatoms chosen from O, S, andN; R¹³ is lower alkyl, lower alkenyl, lower alkynyl, --CF₃, orsubstituted or unsubstituted phenyl, benzyl, or 2-phenethyl; R¹⁴ is H orR¹³ ; R¹⁵ is R³ or halogen; R¹⁶ is H, C₁ -C₄ alkyl, or OH; R¹⁷ is loweralkyl, lower alkenyl, lower alkynyl, or substituted or unsubstitutedphenyl, benzyl, or 2-phenethyl; R¹⁸ is lower alkyl, lower alkenyl, loweralkynyl, --CF₃, or substituted or unsubstituted phenyl, benzyl, or2-phenethyl; R¹⁹ is lower alkyl, lower alkenyl, lower alkynyl, --CF₃, orsubstituted or unsubstituted phenyl, benzyl, or 2-phenethyl; R²⁰ is H,C₁ -C₄ alkyl, substituted or unsubstituted phenyl, benzyl, phenethyl, orpyridinyl or two R²⁰ groups joined to the same N may form a saturatedring of 5 or 6 members containing 1-2 heteroatoms chosen from O, S, andN; R²¹ is H or R¹⁷ ; R²² is R⁴, CHR⁷ OR³, or CHR⁷ SR² ; m and m' areindependently 0-8; n and n' are independently 0 or 1, p and p' areindependently 0-8; m+n+p is 1-10 when r is 1 and X² is O, S, S(O), orS(O)₂ ; m+n+p is 0-10 when r is 1 and X² is CR³ R¹⁶ ; m+n+p is 0-10 whenr is 0; m'+n'+p' is 0-10; r and r' are independently 0 or 1; s is 0-3;Q¹ is --C(O)OR³, 1H(or 2H)-tetrazol-5-yl, -C(O)OR⁶, --C(O)NHS(O)₂ R¹³,--CN, --C(O)NR¹² R¹², --NR²¹ S(O)₂ R¹³, --NR¹² C(O)NR¹² R¹², --NR²¹C(O)R²⁸, --OC(O)NR¹² R¹², --C(O)R¹⁹, --S(O)R¹⁸, --S(O)₂ R¹⁸, --S(O)₂NR¹² R¹², --NO₂, --NR²¹ C(O)OR¹⁷, --C(NR¹² R¹²)=NR¹², --C(R¹³)=NOH; orif Q¹ is --C(O)OH and R²² is --OH, --SH, --CHR⁷ OH or --NHR³, then Q¹and R²² and the carbons through which they are attached may form aheterocyclic ring by loss of water; Q² is OH or NR²⁰ R²⁰ ; W is O, S, orNR³ ; X² and X³ are independently O, S, S(O), S(O)₂, or CR³ R¹⁶ with theproviso that at least one is S or S(O)₂ ; Y is ##STR14## Z¹ and Z² areindependently --HET(--R³ --R⁵)--; HET is the diradical of a benzene, apyridine, a furan, or a thiophene; and the pharmaceutically acceptablesalts thereof.
 2. A compound of claim 1 wherein:R¹ is H, halogen, CF₃,or --CN; R² is C₁ -C₄ alkyl, --CF₃, --CHF₂, --CH₂ F, or two R² groupsjoined to the same carbon may form a ring of up to 6 carbons; R³ is H orR² ; CR³ R²² may be the radical of a standard amino acid; R⁴ is --OR³,--SR³, NR³ R³, NHC(O)CH₃, or R³ ; R⁵ is H or halogen; R⁶ is --(CH₂)_(s)--C(R⁷ R⁷)--(CH₂)_(s) --R⁸ or -CH₂ C(O)NR¹² R¹² ; R⁷ is H or C₁ -C₄alkyl; R⁸ is A) a monocyclic or bicyclic heterocyclic radical containingfrom 3 to 12 nuclear carbon atoms and 1 or 2 nuclear heteroatomsselected from N, S or O and with each ring in the heterocyclic radicalbeing formed of 5 or 6 atoms, or B) the radical W-R⁹ ; R⁹ contains up to20 carbon atoms and is (1) an alkyl group or (2) an alkylcarbonyl group;R¹⁰ is --SR¹¹, --OR¹², or --NR¹² R¹² ; R¹¹ is lower alkyl, --C(O)R¹⁴,unsubstituted phenyl, or unsubstituted benzyl; R¹² is H, R¹¹, or two R¹²groups joined to the same N may form a ring of 5 or 6 members containing1-2 heteroatoms chosen from O, S, and N; R¹³ is lower alkyl, --CF₃, orsubstituted or unsubstituted phenyl, benzyl, or 2-phenethyl; R¹⁴ is H orR¹³ ; R¹⁵ is R³ or halogen; R¹⁶ is H, C₁ -C₄ alkyl, or OH; R²² is R⁴,--CH₂ OR³, or --CH₂ SR² ; m and m' are independently 0-4; n and n' areindependently 0 or 1; p and p' are independently 0-4; m+n+p is 1-9 whenr is 1 and X² is O or S; m+n+p is 0-9 when r is 1 and X² is CR³ R¹⁶ ;m+n+p is 0-9 when r is 0; m'+n'+p'is 1-9; r and r' are independently 0or 1; s is 0-3; Q¹ is --C(O)OR³, 1H(or 2H)-tetrazol-5-yl, --C(O)OR⁶,--C(O)NHS(O)₂ R¹³, --C(O)NR¹² R¹², --NHS(O)₂ R¹³ ; or if Q¹ is C(O)OHand R²² is --OH, --SH, --CH₂ OH or --NHR³ then Q¹ and R²² and thecarbons through which they are attached may form a heterocyclic ring byloss of water; Q² is OH; W is O, S, or NH; X² and X³ are independentlyO, S, or CR³ R¹⁶ ; Y is ##STR15## Z¹ and Z² are independently --HET(--R³--R⁵)--; HET is the diradical of a benzene, pyridine, furan, orthiophene; and the pharmaceutically acceptable salts thereof.
 3. Acompound of claim 1 wherein the R²² α to Q¹ is lower alkyl, CF₃ orsubstituted or unsubstituted phenyl.
 4. A compound of claim 1 of theFormula Ia: ##STR16## wherein: R¹ is H, halogen, CN, or CF₃ ;Rhu 22 isR³, --CH₂ OR³, or --CH₂ SR² ; Q¹ is --C(O)OH, 1H(or 2H)-tetrazol-5-yl,--C(O)NHS(O)₂ R¹³, --C(O)NR¹² R¹², or --NHS(O)₂ R¹³ ; m' is 2 or 3; p'is 0 or 1; m+p is 1-5; and the pharmaceutically acceptable saltsthereof.
 5. A compound of claim 4 wherein m is
 0. 6. A compound of claim4 wherein the carbon α to Q¹ is lower alkyl-substituted.
 7. A compoundof claim 1 of the Formula Ib: ##STR17## wherein: R¹ is H, halogen, CN,or CF₃ ;R²² is R³ , --CH₂ OR³, or --CH₂ SR² ; Q¹ is --C(O)OH, 1H(or2H)-tetrazol-5-yl, --C(O)NHS(O)₂ R¹³, --C(O)NR¹² R¹², or --NHS(O)₂ R¹³ ;m is0, 2, or3; p is0or 1; p' is 1-4; m+p is 0-4; and thepharmaceutically acceptable salts thereof.
 8. A compound of claim 1 ofFormula I' ##STR18## wherein the substituents are as follows:

    __________________________________________________________________________       * R.sup.1                                                                           Y      A               B                                             __________________________________________________________________________     1 RS                                                                              7-Cl                                                                              CHCH.sub.2 CH                                                                        SCH.sub.2 CHMeCO.sub.2 H                                                                      (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH         2 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CHMeCO.sub.2 H                                                                      (CH.sub.2).sub.2 (1,2-phe)(1-c-Bu)OH           3 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2 CH                                                                 SCH.sub.2 CHEtCO.sub.2 H                                                                      (CH.sub.2).sub.2 (4-Cl-1,2-phe)CMe.sub.2                                      OH                                             4 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CHMeCO.sub.2 H                                                                      (1,3-phe)C.sub.2 OH                            5 RS                                                                              7-Cl                                                                              CHCH.sub.2 CH                                                                        S(CH.sub.2).sub.2 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 (1,2-phe)CO.sub.2 H           6 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 (S)CHEtCO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH         7 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 (R)CH(NH.sub.2)Co.sub.2 H                                                           (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH         8 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 (S)CHMeCO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH         9 S 7-Cl                                                                              CH.sub.2 CH2                                                                         SCH.sub.2 (S)CH(n-Pr)CO.sub.2 H                                                               (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        10 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2 CH                                                                 SCH.sub.2 CHEtCO.sub.2 H                                                                      (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        11 RS                                                                              7-Cl                                                                              CHCBr.sub.2 CH                                                                       SCH.sub.2 CHEtCO.sub.2 H                                                                      (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        12 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CMe.sub.2 CO.sub.2 H                                                                (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        13 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CHMeCO.sub.2 H                                                                      (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        14 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.2 CO.sub.2 H                                                                  (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        15 RS                                                                              7-Br                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CHMeCO.sub.2 H                                                                      (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        16 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2)CMe.sub.2 OH                                                                       (CH.sub.2).sub.2 (1,2-phe)CHMeCO.sub.2 H      17 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CHEtCO.sub.2 H                                                                      S(CH.sub.2).sub.2 CMe.sub.2 OH                18 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CHMeCO.sub.2 H                                                                      (CH.sub.2).sub.2 (1,2-phe)C(CF.sub.3).sub.                                    2 OH                                          19 RS                                                                              7-Cl                                                                              CHCH.sub.2 CH                                                                        SCH.sub.2 CHEtCO.sub.2 H                                                                      (CH.sub.2).sub.2 (1,3-phe)CMe.sub.2 OH        20 RS                                                                              7-Cl                                                                              CHCH.sub.2 CH                                                                        SCH.sub. 2 CHEtCO.sub.2 H                                                                     SCH.sub.2 CMe.sub.2 CMe.sub.2 OH              21 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.2 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 (1,2-phe)CO.sub.2 H          22 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.2 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 (1,2-phe)CONH.sub.2          23 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CHMeCO.sub.2 H                                                                      SCH.sub.2 (1,2-phe)CMe.sub.2 OH               24 RS                                                                              7-CF.sub.3                                                                        CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CHMeCO.sub.2 H                                                                      (CH.sub.2).sub.2 (1,4-phe)CMe.sub.2 OH        25 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CH(OMe)CO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        26 RS                                                                              7-Cl                                                                              CHCH.sub.2 CH                                                                        SCH.sub.2 CHEtCO.sub.2 H                                                                      (CH.sub.2).sub.2 (1,2-phe)CH(CF.sub.3)OH      27 RS                                                                              H   CHCH.sub.2 CH                                                                        SCH.sub.2 CHMeCO.sub.2 H                                                                      (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        28 RS                                                                              H   CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CHEtCO.sub.2 H                                                                      (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        29 RS                                                                              7-Br                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CHEtCO.sub.2 H                                                                      (CH.sub.2).sub.2 (4-Br-1,2-phe)CMe.sub.2                                      OH                                            30 RS                                                                              7-CN                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CHEtCO.sub.2 H                                                                      (CH.sub.2).sub.2 (1,2-phe)CMeEtOH             31 RS                                                                              7-Br                                                                              CHCH.sub.2 CH                                                                        SCH.sub.2 CHEtCO.sub.2 H                                                                      (CH.sub.2).sub.2 (1,2-phe)CEt.sub.2 OH        32 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CHMeCO.sub.2 H                                                                      (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2                                           NH.sub.2                                      33 RS                                                                              7-Cl                                                                              CHCH.sub.2 CH                                                                        SCH.sub.2 CHEtCO.sub.2 H                                                                      (CH.sub.2).sub.2 (1,2-phe)CHMeNHMe            34 RS                                                                              7-Br                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CHEtCO.sub.2 H                                                                      (CH.sub.2).sub.2 (1,2-phe)CHMeNMe.sub.2       35 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CHEtCO.sub.2 H                                                                      (CH.sub.2).sub.2 (2,5-fur)CMe.sub.2 OH        36 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CHEtCO.sub.2 H                                                                      (CH.sub.2).sub.2 (2,6-pye)CMe.sub.2 OH        37 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CHEtCO.sub.2 H                                                                      (CH.sub.2).sub.2 (4,2-pye)CMe.sub.2 OH        38 RS                                                                              7-Cl                                                                              CHCH.sub.2 CH                                                                        SCH.sub.2 CHEtCO.sub.2 H                                                                      (2,5-thio)CMe.sub.2 OH                        39 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CHEtCO.sub.2 H                                                                      (3,2-pye)CMe.sub.2 OH                         40 RS                                                                              7-Br                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CHEtCO.sub.2 H                                                                      (1,4-phe)CMe.sub.2 OH                         41 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CHMeCONHS(O).sub.2 Me                                                               (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        42 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CHMeCONH.sub.2                                                                      (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        43 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CHMeTz                                                                              (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        44 RS                                                                              7-Cl                                                                              CHCH.sub.2 CH                                                                        SCH.sub.2 CHEtTz                                                                              (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        45 RS                                                                              7-Cl                                                                              CHCH.sub.2 CH                                                                        SCH.sub.2 CHEtCONHS(O).sub.2 CF.sub.3                                                         (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        46 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CHMeNO.sub.2                                                                        (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        47 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.2 CONHS(O).sub.2 Ph                                                           (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        48 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CHEtCO.sub.2 H                                                                      (CH.sub.2).sub.2 (1,2-phe)CH.sub.2                                            CMe.sub.2 OH                                  49 RS                                                                              7-Cl                                                                              CHCH.sub.2 CH                                                                        SCH.sub.2 CHEtCO.sub.2 H                                                                      (CH.sub.2).sub.3 (1,2-phe)CMe.sub.2 OH        50 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CH(CH.sub.2 CH═CH.sub.2)CO.sub.2 H                                              (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        51 S 7-Cl                                                                              CHCH.sub.2 CH                                                                        SCH.sub.2 CHEtCO.sub.2 H                                                                      (CH.sub.2).sub.2 (1,2-phe)CHMeOH              52 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CH(CH.sub.2 SMe)CO.sub.2 H                                                          (CH.sub.2).sub.2 (1,2-Phe)CMe.sub.2 OH        53 S 7-Cl                                                                              CHCH.sub.2 CH                                                                        SCH.sub.2 CH(c-Pr)CO.sub.2 H                                                                  (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        54 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CH(CH.sub.2 C.tbd.CH)CO.sub.2 H                                                     (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        55 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CHPhCO.sub.2 H                                                                      (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        56 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CHEtCO.sub.2 H                                                                      (1,2-phe)CMe.sub.2 OH                         57 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.2 CMe.sub.2 OH                                                                (1,3-phe)CO.sub.2 H                           58 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.2 CO.sub.2 H                                                                  CH.sub.2 CHOH(1,3-phe)CN.sub.4 H              59 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.2 CO.sub.2 H                                                                  CH.sub.2 CHOH(1,4-phe)CN.sub.4 H              60 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.2 CO.sub.2 H                                                                  CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH         61 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CHCF.sub.3 CO.sub.2 H                                                               CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH         62 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.3 CO.sub.2 H                                                                  (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        63 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub. 2).sub.2 CHMeCO.sub.2 H                                                             (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        64 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(O).sub.2 CH.sub.2 (S)CHEtCO.sub.2 H                                                         (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        65 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CH(CH.sub.2 OMe)CO.sub.2 H                                                          (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        66 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.2 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 (1,2-phe)CO.sub.2 H          67 R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.2 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 (1,2-phe)CO.sub.2 H          68 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 (S)CHEtCO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,3-phe)CMe.sub.2 OH        69 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CHEtCO.sub.2 H                                                                      (CH.sub.2).sub.2 (1,3-phe)(1,1-c-Bu)OH        70 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.2 CMe.sub.2 OH                                                                (CH.sub.2).sub.3 (1,2-phe)COOH                71 R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.2 CO.sub.2 H                                                                  S(CH.sub.2).sub.2 (1,-c-Pen)OH                72 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CH(CH.sub.2 CF.sub.3)CO.sub.2 H                                                     (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        73 S 7-Cl                                                                              CH.sub.2 CH.sub. 2                                                                   S(CH.sub.2).sub.2 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 (4-C1-1,2-phe)CO.sub.2                                       H                                             74 R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 (S)CHEtCONHS(O).sub.2 Me                                                            (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        75 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.2 CMeOH                                                                       (CH.sub.2).sub.2 (1,3-phe)CMe.sub.2                                           CO.sub.2 H                                    76 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.2 CMeOH                                                                       (CH.sub.2).sub.2 (1,3-phe)CHMeCO.sub.2 H      77 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.3 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 (1,2-Phe)CO.sub.2 H          78 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 (S)CHEtCO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,4-phe)CMe.sub.2 OH        79 RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.2 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 (1,3-phe)CN.sub.4 H          80 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.3 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 (1,2-phe)CHMeCO.sub.2 H      81 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.3 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 (1,2-phe)CHMeCONHS(O).sub                                    .2 CH.sub.3                                   82 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.2 CMe.sub.2 OH                                                                (CH.sub.2).sub.3 (1,2-phe)CO.sub.2 H          83 R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(O).sub.2 CH.sub.2 (S)CHEtCO.sub.2 H                                                         (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        84 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.2 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 (4-Cl-1,2-phe)CHMeCO.sub.                                    2 H                                           85 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 (S)CHMeCO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,2-phe)CH.sub.2                                            CMe.sub.2 OH                                  86 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.2 CME.sub.2 OH                                                                (CH.sub.2).sub.2 (1,2-phe)CO.sub.2 Me         87 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.3 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 (4-Cl-1,2-phe)CO.sub.2                                       H                                             88 R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.2 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 (4-Cl-1,2-phe)CO.sub.2                                       H                                             89 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.3 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2                                           CO.sub.2 H                                    90 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.2 CMe.sub.2 OH                                                                (CH.sub.2).sub.3 (R)CHMe.sub.2 CO.sub.2                                       H                                             91 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.3 CEt.sub.2 OH                                                                (CH.sub.2).sub.2 (1,2-phe)CO.sub.2 H          92 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub. 2).sub.3 CEt.sub.2 OH                                                               (CH.sub.2).sub.2 (1,2-phe)CHMeCO.sub.2 H      93 R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCHMeCH.sub.2 CO.sub.2 H                                                                      (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        94 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.3 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 (1,2-phe)CHEtCO.sub.2 H      95 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.3 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 (1,2-phe)CH(n-Pr)CO.sub.2                                     H                                            96 S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.3 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 (1,2-phe)CH(i-Pr)CO.sub.2                                     H                                            97 R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 MeCHMeCO.sub.2 H                                                                    (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        98 R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.2 CMe.sub.2 OH                                                                (CH.sub.2).sub.3 (R)CHMeCO.sub.2 H            99 R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 (S)CHMeCN.sub.4 H                                                                   (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        100                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 (S)CHMeCO.sub.2 H                                                                   (CH.sub.2).sub.2 (3-OH-1,4-phe)CHMeOH         101                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.3 CHMeOH                                                                      (CH.sub.2).sub.2 (1,2-phe)CHMeCO.sub.2 H      102                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(S)CHMeCH.sub.2 CO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        103                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(R)CHMeCH.sub.2 CO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        104                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(S)CHMe(S)CHMeCO.sub.2 H                                                                     (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        105                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(R)CHMe(R)CHMeCO.sub.2 H                                                                     (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        106                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCHEtCH.sub.2 CO.sub.2 H                                                                      (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        107                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.3 CHMeOH                                                                      (CH.sub.2).sub.2 (1,2-phe)CHEtCO.sub.2 H      108                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 (S)CHMeCO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,2-phe)CH(OH)CH.sub.2                                      (OH)Ph                                        109                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCMe.sub.2 CH.sub.2 CO.sub.2 H                                                                (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        110                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CHMeCH.sub.2 CO.sub.2 H                                                             (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        111                                                                              R 7-Cl                                                                              CH.sub.2 CMe.sub.2                                                                   SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 H                                                       (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        112                                                                              S 7-Cl                                                                              CMe.sub.2 CH.sub.2                                                                   SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 H                                                       (CH.sub.2).sub.2 (1,2-phe)CO.sub.2 H          113                                                                              S 7-Cl                                                                              Me.sub.2 H.sub.2 CH.sub.2                                                            S(CH.sub.2).sub.3 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 (1,2-phe)(R)CHEtCO.sub.2                                     H                                             114                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.3 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 (1,2-phe)(S)CHEtCO.sub.2                                     H                                             115                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.3 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 (4-Cl-1,2-phe)CHEtCO.sub.                                    2 H                                           116                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.3 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 (1,2-phe)CEt.sub.2                                           CO.sub.2 H                                    117                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.3 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 (1,2-phe)CH.sub.2                                            CO.sub.2 H                                    118                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.3 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 (1,2-phe)CH(OH)CO.sub.2                                      H                                             119                                                                              S 7-Cl                                                                              CHMeCHMe                                                                             SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 H                                                       (CH.sub.2).sub.2 (1,2-phe)CHEtCO.sub.2 H      120                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.3 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 CHMeCH.sub.2 CO.sub.2 H      121                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CMe.sub.2 CH.sub.2 CO.sub.2 H                                                       (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        122                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.4 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 (1,2-phe)CHEtCO.sub.2 H      123                                                                              S 7-F CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CMe.sub.2 CH.sub.2 CO.sub.2 H                                                       (CH.sub.2).sub.2 (1,2-phe)CO.sub.2 H          124                                                                              S 7-Br                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CMe.sub.2 CH.sub.2 CO.sub.2 H                                                       (CH.sub.2).sub.2 (1,2-phe)CO.sub.2 H          125                                                                              S 7-I CH.sub.2 CH.sub.2                                                                    SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 H                                                       (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        126                                                                              S 7-CF.sub.3                                                                        CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CMe.sub.2 CH.sub.2 CO.sub.2 H                                                       (CH.sub.2).sub.2 (1,2-phe)CHMeCO.sub.2 H      127                                                                              S 7-CN                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CMe.sub.2 CH.sub.2 CO.sub.2 H                                                       (CH.sub.2).sub.2 (1,2-phe)CHEtCO.sub.2 H      128                                                                              S 7-NO.sub.2                                                                        CH.sub.2 CH.sub.2                                                                    SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 H                                                       (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        129                                                                              R 7-N.sub.3                                                                         CH.sub.2 CH.sub.2                                                                    SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 H                                                       (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        130                                                                              RS                                                                              7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.2 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 CMe.sub.2 CH.sub.2                                           CO.sub.2 H                                    131                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(1,2-phe)CH.sub.2 CO.sub.2 H                                                                 (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        132                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.3 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 (1,2-phe)CHEtCO.sub.2 H      133                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.2 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 (1,2-phe)CHEtCO.sub.2 H      134                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.3 CMe(4-Cl-Ph)OH                                                              (CH.sub.2).sub.2 (1,2-phe)CHEtCO.sub.2 H      135                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 (1,2-phe)CMe.sub.2 OH                                                               (CH.sub.2).sub.2 CMe.sub.2 CH.sub.2                                           CO.sub.2 H                                    136                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 H                                                       (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        137                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 (1,1-c-Bu)CH.sub.2 CO.sub.2 H                                                       (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        138                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CMe.sub.2 CHMeCO.sub.2 H                                                            (CH.sub.2).sub.2 1,2-phe)CMe.sub.2 OH         139                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 (1,2-phe)CMe.sub.2 OH                                                               (CH.sub.2).sub.2 CMe.sub.2 CH.sub.2                                           CO.sub.2 H                                    140                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCHMeCMe.sub.2 CH.sub.2 CO.sub.2 H                                                            (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        141                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(1,1-c-Pr)CH.sub.2 CO.sub.2 H                                                                (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        142                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(1,1-c-Pr)CHMeCO.sub.2 H                                                                     (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        143                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(1,1-c-Pr)CH.sub.2 CO.sub.2 H                                                                (CH.sub.2).sub.2 (1,3-phe)CMe.sub.2 OH        144                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(1,1-c-Pr)CH.sub.2 CO.sub.2 H                                                                (CH.sub.2).sub.2 (1,2-phe)(1,1-c-Bu)OH        145                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(1,1-c-Pr)CH.sub.2 CO.sub.2 H                                                                (CH.sub.2).sub.2 (1,3-phe)(1,1-c-Bu)OH        146                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 H                                                       (CH.sub.2).sub.2 (1,3-phe)CMe.sub.2 OH        147                                                                              R 7-Cl                                                                              CHCH.sub.2 CH                                                                        SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 H                                                       (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        148                                                                              R 7-Cl                                                                              CHCH.sub.2 CH                                                                        S(1,1-c-Pr)CH.sub.2 CO.sub.2 H                                                                (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        149                                                                              R 7-Cl                                                                              CHCH.sub.2 CH                                                                        SCMe.sub.2 CH.sub.2 CO.sub.2 H                                                                (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        150                                                                              R 7-Cl                                                                              CHCH.sub.2 CH                                                                        S(1,1-c-Pr)(S)CHMeCO.sub.2 H                                                                  (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        151                                                                              R 7-Cl                                                                              CHCH.sub.2 CH                                                                        S(1,1-c-Pr)CHMeCO.sub.2 H                                                                     (CH.sub.2).sub.2 (1,3-phe)CMe.sub.2 OH        152                                                                              R 7-Cl                                                                              CHCH.sub.2 CH                                                                        S(1,1-c-Pr)CH.sub.2 CO.sub.2 H                                                                (CH.sub.2).sub.2 (1,2-phe)(1,1-c-Bu)OH        153                                                                              R 7-Cl                                                                              CHCH.sub.2 CH                                                                        S(1,1-c-Pr)CH.sub.2 CO.sub.2 H                                                                (CH.sub.2).sub.2 (1,3-phe)(1,1-c-Bu)OH        154                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CHEtCO.sub.2 H                                                                      (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH        155                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 (1,2-phe)CMe.sub.2 OH                                                               CH.sub.2).sub.2 (1,2-phe)CHEtCO.sub.2 H       156                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.2 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 (1,2-phe)CH.sub.2                                            CO.sub.2 H                                    157                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 (1,2-phe)CHMe.sub.2 OH                                                              (CH.sub.2).sub.2 (1,2-phe)CH.sub.2                                            CO.sub.2 H                                    158                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.2 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 (4-Cl-1,2-phe)CH.sub.2                                       CO.sub.2 H                                    159                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 (1,2-phe)CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (4-Cl-1,2-phe)CH.sub.2                                       CO.sub.2 H                                    160                                                                              R 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 CMe.sub.2 CH.sub.2 CO.sub.2 H                                                       (CH.sub.2).sub.4 (1,2-phe)CMe.sub.2 OH        161                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    S(CH.sub.2).sub.3 CMe.sub.2 OH                                                                (CH.sub.2).sub.2 (4-Cl-1,2-phe)CH.sub.2                                       CO.sub.2 H                                    162                                                                              S 7-Cl                                                                              CH.sub.2 CH.sub.2                                                                    SCH.sub.2 (1,2-phe)CMe.sub.2 OH                                                               (CH.sub.2).sub.2 (1,1-c-Pr)CH.sub.2                                           CO.sub.2 H                                    __________________________________________________________________________


9. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 1 and a pharmaceutically acceptablecarrier.
 10. The pharmaceutical composition of claim 9 additionallycomprising an effective amount of a second active ingredient selectedfrom the group consisting of non-steroidal anti-inflammatory drugs;peripheral analgesic agents; cyclooxygenase inhibitors; leukotrieneantagonists; leukotriene bisynthesis inhibitors; H2-receptorantagonists; antihistaminic agents; prostaglandin antagonists;thromboxane antagonists; thromboxane synthetase inhibitors; and ACEantagonists.
 11. A pharmaceutical composition according to claim 10,wherein the second active ingredient is a non-steroidalanti-inflammatory drug.
 12. A pharmaceutical composition of claim 11,wherein the weight ratio of said compound of claim 1 to said secondactive ingredient ranges from about 1000: 1 to 1:
 1000. 13. A method ofpreventing the synthesis, the action, or the release of SRS-A orleukotrienes in a mammal which comprises administering to said mammal aneffective amount of a compound of claim
 1. 14. The method of claim 13wherein the mammal is man.
 15. A method of treating asthma in a mammalcomprising administering to a mammal in need of such treatment atherapeutically effective amount of a compound of claim
 1. 16. A methodof treating inflammatory deseases of the eye in a mammal which comprisesadministering to a mammal in need of such treatment a therapeuticallyeffective amount of a compound of claim
 1. 17. The method of claim 16wherein the mammal is man.